Case 3:12-cv MLC-LHG Document 23 Filed 02/05/13 Page 1 of 25 PageID: 341 UNITED STATES DISTRICT COURT DISTRICT OF NEW JERSEY

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1 Case 3:12-cv MLC-LHG Document 23 Filed 02/05/13 Page 1 of 25 PageID: 341 UNITED STATES DISTRICT COURT DISTRICT OF NEW JERSEY OTSUKA PHARMACEUTICAL CO., LTD. Plaintiff. v. No. 3:12-cv MLC-LHG SILARX PHARMACEUTICALS, INC. Defendant. ANSWER OF SILARX PHARMACEUTICALS, INC. TO OTSUKA PHARMACEUTICAL CO., LTD. S COMPLAINT FOR PATENT INFRINGEMENT Silarx Silarx Pharmaceuticals, Inc. ( Silarx ) Answers Plaintiff Otsuka Pharmaceutical Co., Ltd. ( Otsuka ) Complaint, and alleges as follows: THE PARTIES 1. Otsuka is a corporation organized and existing under the laws of Japan with its corporate headquarters at 2-9 Kanda Tsukasa-machi, Chiyoda-ku, Tokyo, , Japan. Otsuka is engaged in the research, development, manufacture and sale of pharmaceutical products. Silarx is without direct knowledge or information sufficient to form a belief as to the truth of the allegations of Paragraph 1. Accordingly, the allegations are deemed denied. 2. Upon information and belief, Silarx is a corporation organized under the laws of the State of New York, and its principal place of business is located at 19 West Street, Spring Valley, NY

2 Case 3:12-cv MLC-LHG Document 23 Filed 02/05/13 Page 2 of 25 PageID: 342 Admitted. NATURE OF THE ACTION 3. This is an action for infringement of United States Patent Number 6,977,257 ( the 257 patent ), arising under the United States patent laws, Title 35, United States Code, 100 et seq., including 35 U.S.C. 271 and 281. This action relates to Silarx s filing of an Abbreviated New Drug Application ( ANDA ) under Section 505(J) of the Federal Food, Drug and Cosmetic Act ( the Act ), 21 U.S.C. 355(J) seeking U.S. Food and Drug Administration ( FDA ) approval to market a generic pharmaceutical product ( Silarx s generic product ). The allegations of Paragraph 3 are conclusions of law to which no response is required. To the extent that Paragraph 3 alleges facts related only to the actions of Silarx, they are admitted. JURISDICTION AND VENUE 4. This Court has subject matter jurisdiction under 28 U.S.C and 1338(a). The allegations of Paragraph 4 are conclusions of law to which no response is required. To the extent that Paragraph 4 alleges facts, they are admitted. 5. Upon information and belief, this Court has jurisdiction over Silarx because at a minimum it (1) is registered to do business in this judicial district, (2) retains a registered agent in this judicial district, (3) conducts business within this judicial district, (4) directly, or indirectly, manufactures, markets, sells, and distributes generic drugs throughout the United States and in this judicial district, (5) purposefully has conducted 2

3 Case 3:12-cv MLC-LHG Document 23 Filed 02/05/13 Page 3 of 25 PageID: 343 and continues to conduct business in this judicial district, and (6) this judicial district is a likely destination of its generic products. The allegations of Paragraph 5 are conclusions of law to which no response is required. To the extent that Paragraph 5 alleges facts, they are admitted. 6. Otsuka received a letter from Silarx dated August 1, 2012, purporting to include an Offer of Confidential Access for ANDA No Upon information and belief, this Court additionally has jurisdiction over Silarx because it has availed itself of the rights and benefits of this judicial district, having stated in its Offer of Confidential Access that [t]his Offer of Confidential Access shall be governed by the laws of the State of New Jersey. Silarx admits that it transmitted a letter to Otsuka dated August 1, 2012 making an offer of confidential access for ANDA No , and containing the quoted language. The remaining allegations contained in this paragraph are a conclusion of law, to which no response is required. 7. Upon information and belief, venue is proper in this judicial district under 28 U.S.C. 1391(c) and (d), and 1400(b). The allegations of Paragraph 7 are conclusions of law to which no response is required. To the extent that Paragraph 7 alleges facts, they are admitted. FIRST COUNT FOR PATENT INFRINGEMENT 8. The U.S. Patent and Trademark Office ( PTO ) issued the 257 patent on December 20, 2005, entitled Aripiprazole Oral Solution. A copy of the 257 patent is attached as Exhibit A. 3

4 Case 3:12-cv MLC-LHG Document 23 Filed 02/05/13 Page 4 of 25 PageID: 344 Silarx is without direct knowledge or information sufficient to form a belief as to the truth of the allegations of Paragraph 8, other than that a copy of the 257 patent was attached to the Complaint as Exhibit A. Accordingly, all other allegations are deemed denied. 9. The 257 patent is assigned to Otsuka. Otsuka is the owner of the 257 patent as recorded by the PTO at Reel , Frame Admitted only at the present time, the records of the PTO reflect that Otsuka is the assignee of the 257 patent. 10. The 257 patent expires on October 24, 2022 (including pediatric exclusivity). Admitted. 11. The 257 patent claims, inter alia, oral aripiprazole solutions. The 257 patent is a record of the United States Patent and Trademark Office, and the scope and meaning of its claims are the subject of Otsuka s Complaint against Silarx, which accordingly denies this averment. 12. Otsuka is the holder of NDA No for aripiprazole oral solution, which the FDA approved on December 10, The Orange Book lists the 257 patent for NDA No Admitted. 13. Otsuka manufactures and sells aripiprazole oral solution in the United States under the trademark Abilify. Silarx is without knowledge or information sufficient to form a belief as to the truth of the allegations of Paragraph 13 which are wholly within the knowledge of Otsuka. Upon information and belief, Abilify is either manufactured or sold in the 4

5 Case 3:12-cv MLC-LHG Document 23 Filed 02/05/13 Page 5 of 25 PageID: 345 United States by Otsuka America Pharmaceutical, Inc. and/or Bristol-Myers Squibb Company. Accordingly, the allegations of paragraph 13 are deemed denied. 14. Upon information and belief, Silarx filed with the FDA ANDA No , under Section 505(j) of the Act, 21 U.S.C. 355(j). Admitted. 15. Upon information and belief, Silarx s ANDA No seeks FDA approval to sell in the United States Silarx s generic product. Admitted. 16. Otsuka received a letter from Silarx dated August 1, 2012, purporting to include a Notice of Certification for ANDA No ( Silarx s letter ) under 21 U.S.C. 355(j)(2)(a)(vii)(IV), 21 C.F.R (a)(12)(i)(A)(4) and 21 C.F.R (c). Silarx is without knowledge or information sufficient to form a belief as to the truth of the allegations of Paragraph 16 which are wholly within the knowledge of Otsuka. Accordingly, they are deemed denied. 17. Silarx s letter alleges that the active ingredient in Silarx s generic product for which it seeks approval is aripiprazole. Admitted. 18. Upon information and belief, Silarx s generic product will, if approved and marketed, infringe at least one claim of the 257 patent. Denied. By way of further explanation, Silarx incorporates herein by this reference, as if set forth in full the relevant text of its letter dated August 1, 2012, addressed to Otsuka, which is attached hereto as Exhibit A. 5

6 Case 3:12-cv MLC-LHG Document 23 Filed 02/05/13 Page 6 of 25 PageID: Under 35 U.S.C. 27l(e)(2)(A), Silarx has infringed at least one claim of the 257 patent by submitting, or causing to be submitted to the FDA, ANDA No seeking approval for the commercial marketing of Silarx s generic product before the expiration date of the 257 patent. Denied. By way of further explanation, Silarx incorporates herein by this reference, as if set forth in full the relevant text of its letter dated August 1, 2012, addressed to Otsuka, which is attached hereto as Exhibit A. AFFIRMATIVE DEFENSES Further answering the Complaint and as additional defenses hereto, Silarx asserts the following Affirmative Defenses, without assuming the burden of proof when such burden would otherwise be on Otsuka. First Affirmative Defense (Failure to State a Claim) The Complaint fails to state a cause of action against Silarx upon which relief can be granted. Second Affirmative Defense (Noninfringement) Silarx does not, and has not, infringed any valid and enforceable claim of the 257 patent, directly or indirectly, literally or under the doctrine of equivalents. Third Affirmative Defense (Invalidity) The claims of the 257 patent as properly construed are invalid for failure to comply with one or more of the requirements of 35 U.S.C. 101 et seq., including, without limitation, the conditions of patentability set forth in 101, 102, 103, and/or

7 Case 3:12-cv MLC-LHG Document 23 Filed 02/05/13 Page 7 of 25 PageID: 347 Fourth Affirmative Defense (Privileged Conduct) Upon information and belief, Otsuka s claims are barred, in whole or in part, because any or all of Silarx s conduct has been lawful, justified, and/or privileged. Fifth Affirmative Defense (Failure to Mitigate) Upon information and belief, Otsuka failed to mitigate or attempt to mitigate damages, if in fact any damages have been or will be sustained; therefore, any recovery by Otsuka must be diminished or barred. Sixth Affirmative Defense (Waiver, Laches, Estoppel) Upon information and belief, Otsuka is barred from enforcing the 257 patent against Silarx under the doctrines of waiver, laches, and/or estoppel. Seventh Affirmative Defense (Prosecution History Estoppel) Upon information and belief, Otsuka is barred from enforcing the 257 patent against Silarx under the doctrine of prosecution history estoppel. Eighth Affirmative Defense (Unclean Hands) Upon information and belief, Otsuka is barred from enforcing the 257 patent against Silarx on the basis of unclean hands. In addition to the Affirmative Defenses described above, Silarx specifically reserves the right to allege additional affirmative defenses, as they become known. PRAYER FOR RELIEF WHEREFORE, Silarx prays that this Court grant relief and order: a. That the Complaint be dismissed in its entirety, with prejudice; b. That no relief shall issue to Otsuka; 7

8 Case 3:12-cv MLC-LHG Document 23 Filed 02/05/13 Page 8 of 25 PageID: 348 c. That Otsuka shall take nothing by reason of its Complaint; d. That Silarx be awarded damages; e. That Silarx be awarded its costs, attorneys fees, expenses, and such other further relief as may be just and proper; f. That this action be deemed exceptional under 35 U.S.C. 285, and judgment be entered awarding Silarx its costs and reasonable fees; and, g. Such other relief as the Court may deem just and proper. JURY TRIAL DEMAND In accordance with Federal Rule of Civil Procedure 38, Silarx demands a trial by jury on all issues and claims so triable. Dated: February 5, 2013 /s/ Ralph Jacobs Jacobs Singer Kivitz & Herman LLC 34 Tanner Street Haddonfield, NJ rjacobs@jskhlaw.com Lawrence A. Husick (pro hac pending) Lipton, Weinberger & Husick P.O. Box 587 Southeastern, PA lhusick@lwh-law.com Counsel for Silarx Pharmaceuticals, Inc. 8

9 Case 3:12-cv MLC-LHG Document 23 Filed 02/05/13 Page 9 of 25 PageID: 349 Exhibit A Relevant Portions of Silarx Pharmaceuticals Letter to Otsuka Dated August 1, 2012 Infringement Analysis Of Bristol-Myers Squibb US patent no. 6,977,257 Applicable Case Law: For a claim to be literally infringed by an accused product or method, every limitation set forth in the claim must be found in the accused product, exactly. Southwall Technologies v. Cardinal IG Co., 54 F.3d 1570 (Fed. Cir. 1995). An accused product that does not literally infringe a claim may nonetheless infringe under the doctrine of equivalents if " it performs substantially the same function in substantially the same way to obtain the same result." Graver Tank & Mfg. Co. v. Linde Air Prods. Co., 339 U.S. 605, 608, 70 S.Ct. 854, 856, 94 L.Ed. 1097, 85 USPQ 328, 330 (1950). An element in the accused device is equivalent to a claim limitation if the only differences between the two are insubstantial. Honeywell Int l Inc. v. Hamilton Sundstrand Corp., 370 F.3d 1131, 1139 (Fed.Cir.2004); Pall Corp. v. Micron Separations, Inc., 66 F.3d 1211, 1218 (Fed.Cir.1995), cert. denied, U.S. 117 S.Ct (1997). a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers ; 35 U.S.C. 112, 4. As a general rule, dependent claims cannot be found infringed unless the claims from which they depend have been found to have been infringed. Wahpeton Canvas Co. v. Frontier, Inc., 870 F. 2d 1546 (Fed. Cir. 1989); Jeneric/Pentron v. Dillon Co. and Chemichel, Inc., 205 F. 3d 1377 (Fed. Cir. 2000); Minnesota Mining And Manufacturing Co. v. Chemque, Inc., 303 F. 3d 1294 (Fed. Cir. 2002). [A] narrowing amendment made to satisfy any requirement of the Patent Act may give rise to an estoppel.... Estoppel arises when an amendment is made to secure the patent and the amendment narrows the patent s scope. [If] a 112 amendment is necessary and narrows the patent s scope - even if only for the purpose of better description - estoppels may apply. A patentee who narrows a claim as a condition for obtaining a patent disavows his claim to the broader subject matter, whether the amendment was made to avoid the prior art or to comply with 112. We must regard the patentee as having conceded an inability to claim the broader subject matter or at least as having abandoned his right to appeal a rejection. In either case estoppels may apply. A patentees decision to narrow his claims through amendment may be presumed to be a general disclaimer of the territory between the original claim and the amended claim. An estoppel triggered by a narrowing amendment for a substantial reason related to patentability... bars the application of the doctrine of equivalents as to that element, 9

10 Case 3:12-cv MLC-LHG Document 23 Filed 02/05/13 Page 10 of 25 PageID: 350 i.e., results in a surrender of all equivalents for the particular claim element narrowed by the amendment, and therefore a finding of non-infringement for an alleged equivalent that falls within the scope of the claim surrendered, unless the patentee can show that [t]he equivalent may have been unforeseeable at the time of the application; the rationale underlying the amendment may bear no more than a tangential relation to the equivalent in question; or there may have been some other reason suggesting that the patentee could not reasonably be expected to have described the insubstantial substitute in question. Festo Corp. v. Shoketsu Kinzoku Kogyo Kabushiki Co., Ltd., 535 U.S. 722, 152 L.Ed.2d 944 (2002). Rewriting a dependent claim as an independent claim will trigger the Festo presumption of prosecution history estoppel. Ranbaxy Pharms. Inc. v. Apotex Inc., 350 F. 3d 1235, 69 U.S.P.Q.2d 1086 (Fed. Cir. 2003). If a limitation was added to a claim in a manner that narrowed that claim, the Festo presumption [of prosecution history estoppel] applies to all claims containing [that same limitation], regardless of whether the claim was or was not amended during prosecution. Deering Precision Instruments, LLC v. Vector Distribution Systems, Inc., 347 F. 3d 1314, 1326 (Fed. Cir. 2003), cert. denied, 2004 U.S. LEXIS 1126 (U.S. Feb. 23, 2004). The rewriting of a dependent claim in independent form, coupled with the cancellation of the original independent claim, is a narrowing amendment under Festo, supra. A patentee is presumptively barred from using the doctrine of equivalents for the additional element found in the original dependent claim.... a narrowing amendment to a patent claim that adds an additional claim limitation creates a presumptive surrender of equivalents the addition of a new claim limitation can give rise to a presumption of prosecution history estoppels, just like an amendment that narrows a preexisting claim limitation. In either case, the narrowing amendment, if made for a reason related to patentability, will give rise to a presumption of surrender. If only narrowing amendments to pre-existing claim limitations could give rise to the presumption, the purpose of preventing patentees from recapturing conceded during prosecution would be undermined. Astute practitioners could, through clever claim drafting, elect to treat most, if not all amendments as merely adding new claim limitations rather than narrowing preexisting ones. For these reasons we hold that an amendment adding a new claim limitation constitutes a narrowing amendment that may give rise to an estoppel. Honeywell International Inc. v. Hamilton Sundstrand Corporation, 370 F.3d 1131 (Fed. Cir. 2004)... Among the rules from the original Festo en banc decision that were unchanged by the Supreme Court and reaffirmed by this court in Festo IX was our holding that cancellation of claims for reasons related to patentability in favour of claims with a narrower literal scope has the same presumptive effect on claim limitations as amending 10

11 Case 3:12-cv MLC-LHG Document 23 Filed 02/05/13 Page 11 of 25 PageID: 351 the claims directly. See Festo Corp. v. Shoketsu Kinzoku Kogyo Kabushiki Co., 234 F.3d 558 (Fed. Cir. 2001) (en banc) (Festo VI). In addition, our decision in Festo IX reaffirmed that a narrowing amendment made to comply with any provision of the Patent Act, including a voluntary amendment (or cancellation), may give rise to prosecution history estoppel. Festo Corp. v. Shoketsu Kinzoku Kogyo Kabushiki Co.,344 F.3d 1359 (Fed. Cir. 2003) (en banc) (Festo IX). Applying those principles to this case, we hold that it is immaterial that the claims at issue (amended claims 13 and 14 that were narrower than cancelled claims 1, 2, 5 and 6) were not themselves amended to avoid patentability rejections, because broader claims 1, 2, 5 and 6 which addressed the same claim limitations at issue in this case. were cancelled in response to a rejection for unpatentability,. In that context, the cancellation of claims 1, 2, 5 and 6 created a rebuttable presumption that all subject matter between the pertinent limitations of the original claims and those of the final, issued claims was surrendered. Mycogen Plant Sci. v. Monsanto Co., 2004 U.S. App. LEXIS 3001 (Fed. Cir. Feb. 20, 2004). Infringement Analysis Silarx Pharmaceuticals Generic Aripiprazole Oral Solution Composition The composition of Silarx Pharmaceuticals generic Aripiprazole Oral Solution listed in Silarx Pharmaceuticals ANDA no is as follows: Excipients Amount per 1 ml Function Aripiprazole 1 mg (anhydrous) Active ingredient Orange Flavor ml Flavoring agent Butylated Hydroxyanisole 0.1 mg Antioxidant Phosphoric acid 8.5% ml Buffering agent to maintain ph in range Propylene Glycol, USP 0.6 ml Solvent Propylparaben, NF 0.2 mg Preservative Methylparaben, NF 1.8 mg Preservative Sucralose, USP 1 mg Sweetening agent Sodium hydroxide... To adjust ph Purified Water, USP QS to make 1 ml Co-solvent Bristol-Myers Squibb s US patent no. 6,977,257 titled Aripiprazole Oral Solution recites the following three (3) independent claims: claims 1, 10 and 13. Claim 1 of Bristol-Myers Squibb s 257 patent recites: A pharmaceutical solution suitable for oral administration comprising aripiprazole, a pharmaceutically suitable solvent system comprised of one or more agents selected from the group 11

12 Case 3:12-cv MLC-LHG Document 23 Filed 02/05/13 Page 12 of 25 PageID: 352 consisting of water, ethanol, glycerin, propylene glycol and sorbitol, one or more tasteenhancing/masking agents and one or more agents selected from the group consisting of lactic acid, acetic acid, tartaric acid and citric acid, wherein said solution has a ph from 2.5 to 4.0. Claim 10 of Bristol-Myers Squibb s 257 patent recites: A pharmaceutical solution suitable for oral administration comprising aripiprazole, a pharmaceutically suitable solvent system, one or more taste enhancing/masking agents and lactic acid, wherein said solution has ph from 2.5 to 4.5. Claim 13 of Bristol-Myers Squibb s 257 patent recites: A pharmaceutical solution suitable for oral administration comprising aripiprazole, glycerin, lactic acid, propylene glycol, methylparaben, propylparaben, sucrose, fructose and water. Bristol-Myers Squibb s 257 patent also recites the following dependent claims: claims 2-9 which depend on claim 1; and claims which depend on claim 10. Therefore, if independent claim 1 and 10 of Bristol-Myers Squibb 257 patent are not infringed by Silarx Pharmaceuticals generic aripiprazole oral solution drug product, neither will Bristol-Myers Squibb dependent claims 2-9, and be infringed by Silarx Pharmaceuticals generic aripiprazole oral solution drug product. Wahpeton Canvas Co. v. Frontier, Inc., 870 F. 2d 1546 (Fed. Cir. 1989); Jeneric/Pentron v. Dillon Co. and Chemichel, Inc., 205 F. 3d 1377 (Fed. Cir. 2000); Minnesota Mining And Manufacturing Co. v. Chemque, Inc., 303 F. 3d 1294 (Fed. Cir. 2002). Difference between lactic acid (recited in claim 1, 10 and 13 as a component of the solvent system in Bristol-Myers Squibb 257 patent) and phosphoric acid (used as a component in Silarx Pharmaceuticals generic aripiprazole oral solution drug product) 1) Difference in class of compounds Lactic acid Lactic acid belongs to an organic, carboxylic acid class of compounds Phosphoric acid Phosphoric acid belongs to the inorganic, mineral acid class of compounds 2) Difference in structure of the compounds Lactic acid The structure of lactic acid, C 3 H 6 O 3 is an organic structure. Phosphoric acid The structure of phosphoric acid, H 3 PO 4 an inorganic structure. 12 Phosphoric acid has three hydroxyl groups

13 Case 3:12-cv MLC-LHG Document 23 Filed 02/05/13 Page 13 of 25 PageID: 353 Lactic acid has a hydroxyl group adjacent to the carboxyl group (COOH), making it an alpha hydroxyl acid. attached to phosphorous 3) Difference in the way the compounds function Lactic acid Tartaric acid, malic acid and citric acid are chelating agent (Ref.: BMS patent application 10/131,304, page 13, line 6-9). Lactic acid belongs to the same class of compounds as tartaric acid, malic acid and citric acid and functions as a chelating agent. Chelating agents binds or attach to metal cations (for eg., Mg + 2 ) to form a chelate complex thereby effectively removing them from the solution and inhibiting undesirable events that require the presence of those cations. Phosphoric acid Phosphoric acid functions as a buffering agent to maintain the ph of the Aripiprazole Oral Solution in the 5.0 to 5.8 ph range. References: Lactic acid, Wikipedia, Phosphoric acid, Wikipedia, Handbook of Chemistry and Physics, CRC Press, Ann Arbor, Michigan. The Merck Index, Thirteenth Edition, Merck & Co, Rahway, New Jersey, USA, Remington s Pharmaceutical Sciences Summary of Prosecution History of Bristol-Myers Squibb s 257 Patent On Apr. 24, 2002, Bristol-Myers Squibb filed a patent application titled Aripiprazole Oral Solution with the United States Patent and Trademark Office ( USPTO ). The application was assigned patent application no. 10/131,304. On July 10, 2003, USPTO issued the first office action rejecting all the claims in view of the Duggar reference. On Oct. 8, 2003, Bristol-Myers Squibb filed a response to the July 10, 2003 office action. Bristol-Myers Squibb cancelled dependent claim 7 and entered the limitation consisting of ethanol, glycerin, propylene glycol and sorbitol of claim 7 in independent claim 1. Also, Bristol-Myers Squibb cancelled dependent claims 2, 6-9, 12-14, and 16 that recited, in part, that the solvent system comprises polyethylene glycol, propylene glycol, glycerin, and water. Bristol-Myers Squibb also cancelled independent claim 17 that recited a composition comprising the active aripiprazole and lactic acid. New claims were presented; new independent claim 21 issued as claim 13 in the 257 patent. 13

14 Case 3:12-cv MLC-LHG Document 23 Filed 02/05/13 Page 14 of 25 PageID: 354 On Feb. 4, 2004, responsive to the amendment filed on Oct. 8, 2003, US PTO issued the second office action rejecting all of the pending claims and made the office action final. On April 9, 2004, Bristol-Myers Squibb filed a reply after the final rejection pursuant to 37 CFR 116 and traversed the section 103 rejection of the claims. On May 10, 2004, US PTO issued an Advisory Action affirming the rejection of all the claims. On March 4, 2005, US PTO issued an office action allowing claims 10, 11, 15 and 21 and rejected claims 1, 3-5, 18-20, 22 and 23 as being anticipated by US Patent No. 5,686,440. On Apr. 7, 2005 Bristol-Myers Squibb filed a response showing that the active ingredient in US Patent No. 5, is not aripiprazole. Patent application 10/131,304 was subsequently allowed and issued as the 257 patent. Infringement analysis of claim 1 of Bristol-Myers Squibb s US patent no. 6,977,257 Claim 1 of Bristol-Myers Squibb s 257 patent recites 4 elements: 1) A pharmaceutical solution suitable for oral administration comprising aripiprazole, 2) a pharmaceutically suitable solvent system comprised of one or more agents selected from the group consisting of water, ethanol, glycerin, propylene glycol and sorbitol, 3) one or more taste-enhancing/masking agents and one or more agents selected from the group consisting of lactic acid, acetic acid, tartaric acid and citric acid, and 4) wherein said solution has a ph from 2.5 to 4.0. A claim comparison chart for claim 1 of Bristol-Myers Squibb s 257 patent versus Silarx Pharmaceuticals generic Aripiprazole Oral Solution is tabulated below: Bristol-Myers Squibb s 257 patent, claim 1 A pharmaceutical solution suitable for oral administration comprising aripiprazole, Active: aripiprazole Solvent system: one or more agents selected from the group consisting of water, ethanol, glycerin, propylene glycol and sorbitol ph adjustment excipients: one or more agents Silarx Pharmaceuticals generic Aripiprazole Oral Solution Aripiprazole Solvent system: Water, propylene glycol Not Found In Silarx s generic Aripiprazole Oral Solution Ethanol, glycerin, and sorbitol Phosphoric acid 14

15 Case 3:12-cv MLC-LHG Document 23 Filed 02/05/13 Page 15 of 25 PageID: 355 selected from the group consisting of lactic acid, acetic acid, tartaric acid and citric acid one or more taste-enhancing/masking agents ph range of drug product solution: wherein the solution has a ph from 2.5 to 4.0 Not Found In Silarx s generic Aripiprazole Oral Solution: lactic acid, acetic acid, tartaric acid and citric acid either literally or under the doctrine of equivalents PFC 9620 orange flavor and sucralose ph range: 5.0 to 5.8 The limitation one or more agents selected from the group consisting of lactic acid, acetic acid, tartaric acid and citric acid in the second limitation of claim 1 of Bristol-Myers Squibb 257 patent is not found in Silarx Pharmaceuticals Aripiprazole Oral Solution that uses phosphoric acid as the ph buffering agent. Accordingly, for this additional reason Silarx Pharmaceuticals claim 1 of Bristol-Myers Squibb 257 patent is not literally infringed by Silarx Pharmaceuticals generic Aripiprazole Oral Solution. Furthermore, the phosphoric acid used in Silarx Pharmaceuticals generic Aripiprazole Oral Solution does not infringe the limitation one or more agents selected from the group consisting of lactic acid, acetic acid, tartaric acid and citric acid in the second limitation of claim 1 of Bristol-Myers Squibb 257 patent for the reasons enumerated below. First, the phosphoric acid used to adjust the ph of the Aripiprazole Oral Solution does not function in substantially the same way to obtain the same result as the lactic acid recited in claim 1; Graver Tank; supra. As shown in the table on pages 5-6 of this letter, phosphoric acid is an inorganic acid and is distinguishable from lactic acid, acetic acid, tartaric acid and citric acid which are organic acids. Also, the inorganic structure of phosphoric acid is different from the organic structure of lactic acid, acetic acid, tartaric acid and citric acid. Furthermore, tartaric acid, malic acid and citric acid are chelating agents (Ref.: BMS patent application 10/131,304, page 13, line 6-9). Lactic acid belongs to the same class of compounds as tartaric acid, malic acid and citric acid and functions as a chelating agent. Chelating agents bind or attach to metal cations (e.g., Mg 2 + ) to form a chelate complex thereby effectively removing them from the solution and inhibiting undesirable events that require the presence of those cations. Accordingly, the way phosphoric acid functions is distinguishable from the way lactic acid functions. Also, the function of phosphoric acid in Silarx Pharmaceuticals generic Aripiprazole Oral Solution is distinguishable from the function of lactic acid, acetic acid, tartaric acid and citric acid in the second limitation of claim 1 of Bristol-Myers Squibb 257 patent. In contrast to Silarx Pharmaceuticals lactic acid that provides a high to moderate acidic environment in the pharmaceutical solution, phosphoric acid functions as a buffering agent to maintain the ph of the Aripiprazole Oral Solution in the 5.0 to 5.8 range. Also, the result achieved by Silarx Pharmaceuticals lactic acid is distinguishable from the result achieved by the lactic acid, acetic acid, tartaric acid and citric acid in the second 15

16 Case 3:12-cv MLC-LHG Document 23 Filed 02/05/13 Page 16 of 25 PageID: 356 limitation of claim 1 of Bristol-Myers Squibb 257 patent. Use of the lactic acid, acetic acid, tartaric acid and citric acid results in a high to moderate acidic pharmaceutical solution; in contrast, phosphoric acid functions as a buffering agent to maintain the Aripiprazole Oral Solution in the mildly acidic 5.0 to 5.8 ph range. Accordingly, Silarx Pharmaceuticals phosphoric acid in their generic Aripiprazole Oral Solution does not infringe the second limitation one or more agents selected from the group consisting of lactic acid, acetic acid, tartaric acid and citric acid in claim 1 of Bristol-Myers Squibb 257 under the doctrine of equivalents. Furthermore, the fourth limitation wherein the solution has a ph from 2.5 to 4.0 in claim 1 of Bristol-Myers Squibb s 257 patent is not found in Silarx Pharmaceutical s Aripiprazole Oral Solution which has a ph of 5.0 to 5.8. Accordingly, Silarx Pharmaceuticals Aripiprazole Oral Solution of ph of does not literally infringe the fourth limitation wherein said solution has a ph from 2.5 to 4.0 of claim 1 of Bristol-Myers Squibb s 257 patent. Furthermore, Silarx Pharmaceuticals Aripiprazole Oral Solution does not infringe the fourth limitation wherein the solution has a ph from 2.5 to 4.0 in claim 1 of Bristol-Myers Squibb s 257 patent under the doctrine of equivalents for the following reasons. The function of the 2.5 to 4.0 ph range in claim 1 is to maintain the pharmaceutical solution at a high to moderate acidic state. In contrast the function of the ph range in Silarx Pharmaceuticals Aripiprazole Oral Solution is to maintain the solution at a slightly acidic, buffering state. Also, the way the pharmaceutical solution in claim 1 is adjusted to ph is distinguishable from the way the Silarx Pharmaceutical s Aripiprazole Oral Solution is adjusted to The pharmaceutical solution in claim 1 is adjusted to a ph of by the use of organic acids from the group consisting of lactic acid, acetic acid, tartaric acid and citric acid; in contrast Silarx Pharmaceuticals Aripiprazole Oral Solution is adjusted to a ph of by an inorganic phosphoric acid. Furthermore, the result achieved by the two acids is different. Lactic acid provides a chelating action in claim 1; in contrast, phosphoric acid provides a buffering action in Silarx Pharmaceutical s Aripiprazole Oral Solution. Furthermore, equivalents of the limitations a suitable solvent system, one or more agents selected from the group consisting of lactic acid, acetic acid, tartaric acid and citric acid and a ph of 2.5 to 4.0 for the aripiprazole oral solution are not available to Bristol-Myers Squibb under the doctrine of equivalents, under Festo, supra., for the reason enumerated below. Claim 1 as originally filed in Bristol-Myers Squibb s patent application 10/131,304 recites: 1. A pharmaceutical solution suitable for oral administration comprising aripiprazole, a pharmaceutically suitable solvent system, one or taste-enhancing/masking agents and one or more agents selected from the group consisting of lactic acid, acetic acid, tartaric acid and citric acid, wherein said solution has ph from To obtain an allowance of claim 1 as originally filed, claim 1 was narrowed by Bristol-Myers Squibb during prosecution by cancelling claims 2 and 7 and entering the 16

17 Case 3:12-cv MLC-LHG Document 23 Filed 02/05/13 Page 17 of 25 PageID: 357 ph 4.0 limitation from claim 2 and the ethanol, glycerin and propylene glycol limitations from claim 7 into claim 1. Also, there is no showing by Bristol-Myers Squibb that Silarx Pharmaceuticals equivalents of the limitations a pharmaceutically suitable solvent system, and a ph of 2.5 to 4.5 recited in original claim 1 filed in patent application 10/131,304 were unforeseeable at the time of the application; or, the rationale underlying the amendment bears no more than a tangential relation to the equivalent in question; or, there was some other reason that Bristol-Myers Squibb could not reasonably be expected to have described the insubstantial substitute in question. Therefore, equivalents of the following limitations in claim 1 of Bristol-Myers Squibb s patent application no. 10/131,304 are not available to Bristol Myers-Squibb under Festo, supra: - a pharmaceutically suitable solvent system, and - solution ph from Accordingly, Silarx Pharmaceuticals use of: - phosphoric acid as a ph buffering agent in Silarx Pharmaceuticals generic Aripiprazole Oral Solution does not infringe the third element one or more agents selected from the group consisting of lactic acid, acetic acid, tartaric acid and citric acid in claim 1 of Bristol-Myers Squibb s 257 patent, and - a solution ph of in Silarx Pharmaceuticals generic Aripiprazole Oral Solution does not infringe the solution ph of 2.5 [to] 4.0 in claim 1 of Bristol-Myers Squibb s 257 patent under the doctrine of equivalents. Festo, supra.; Ranbaxy Pharms., supra; Honeywell International Inc., supra; Mycogen Plant Sci., supra. Accordingly, for one or more of the reasons presented above, Silarx Pharmaceuticals Aripiprazole Oral Solution does not infringe claim 1 of Bristol-Myers Squibb s 257 patents either literally, or under the doctrine of equivalents. Infringement analysis of claim 2 of Bristol-Myers Squibb s US patent no. 6,977,257 Claim 2 of Bristol-Myers Squibb s 257 patent recites: A pharmaceutical solution according to claim 1 wherein said other agent is lactic acid. Claim 2 of the 257 patent is dependent on claim 1. Dependent claim 2 contains all the limitations of claim 1 on which it depends and also the limitation in claim 2; 35 U.S.C. 112, 4. Since Silarx Pharmaceuticals generic Aripiprazole Oral Solution drug product does not infringe claim 1 of the 257 patent, dependent claim 2 of the 257 patent is also not infringed literally or under the doctrine of equivalents by Silarx Pharmaceuticals generic Aripiprazole Oral Solution; Wahpeton Canvas Co. v. Frontier, Inc.; Jeneric/Pentron v. Dillon Co. and Chemichel, Inc. and Minnesota Mining And Manufacturing Co. v. Chemque, Inc, supra. Infringement analysis of claim 3 of Bristol-Myers Squibb s US patent no. 6,977,257 17

18 Case 3:12-cv MLC-LHG Document 23 Filed 02/05/13 Page 18 of 25 PageID: 358 Claim 3 of Bristol-Myers Squibb s 257 patent recites: A pharmaceutical solution according to claim 2 wherein said lactic acid is present at concentrations selected from the group of ranges consisting of 0.7 mg/ml to 18 mg/ml, 3.5 mg/ml to 14.5 mg/ml and 5.4 mg/ml to 9 mg. Claim 3 of the 257 patent is dependent on claim 2 which in turn is dependent on claim 1. Claim 3 contains all the limitations of claim 2 on which it depends and also the limitations in claim 1; 35 U.S.C. 112, 4. Since Silarx Pharmaceuticals generic Aripiprazole Oral Solution does not infringe claims 1 and 2 of the 257 patent, dependent claim 3 of the 257 patent is also not infringed literally or under the doctrine of equivalents by Silarx Pharmaceuticals generic Aripiprazole Oral Solution; Wahpeton Canvas Co. v. Frontier, Inc.; Jeneric/Pentron v. Dillon Co. and Chemichel, Inc. and Minnesota Mining And Manufacturing Co. v. Chemque, Inc, supra. Infringement analysis of claim 4 of Bristol-Myers Squibb s US patent no. 6,977,257 Claim 4 of Bristol-Myers Squibb s 257 patent recites: A pharmaceutical solution according to claim 1 wherein aripiprazole is present at concentrations selected from the group of ranges consisting of 0.05 mg/ml to 6 mg/ml, 0.1 mg/ml to 3 mg/ml, 0.25 mg/ml to 2 mg/ml and 0.75 mg/ml to 1.5 mg/ml. Claim 4 of the 257 patent is dependent on claim 1. Dependent claim 4 contains all the limitations of claim 1 on which it depends and also the limitations in claim 4; 35 U.S.C. 112, 4. Since Silarx Pharmaceuticals generic Aripiprazole Oral Solution drug product does not infringe claim 1 of the 257 patent, dependent claim 4 of the 257 patent is also not infringed literally or under the doctrine of equivalents by Silarx Pharmaceuticals generic Aripiprazole Oral Solution. Wahpeton Canvas Co. v. Frontier, Inc.; Jeneric/Pentron v. Dillon Co. and Chemichel, Inc.; and Minnesota Mining And Manufacturing Co. v. Chemque, Inc, supra. Infringement analysis of claim 5 of Bristol-Myers Squibb s US patent no. 6,977,257 Claim 5 of Bristol-Myers Squibb s 257 patent recites: A pharmaceutical solution according to claim 1 wherein said pharmaceutically suitable solvent system is comprised of propylene glycol, glycerin and water each being present in ratios of : : w/w respectively. Claim 5 of the 257 patent is dependent on claim 1. Dependent claim 5 contains all the limitations of claim 1 on which it depends and also the limitation in claim 5; 35 U.S.C. 112, 4. Since Silarx Pharmaceuticals generic Aripiprazole Oral Solution does not infringe claim 1 of the 257 patent, dependent claim 5 of the 257 patent is also not infringed literally or under the doctrine of equivalents by Silarx Pharmaceuticals generic Aripiprazole Oral Solution; Wahpeton Canvas Co. v. Frontier, Inc.; Jeneric/Pentron v. Dillon Co. and Chemichel, Inc. and Minnesota Mining And Manufacturing Co. v. Chemque, Inc, supra. 18

19 Case 3:12-cv MLC-LHG Document 23 Filed 02/05/13 Page 19 of 25 PageID: 359 Infringement analysis of claim 6 of Bristol-Myers Squibb s US patent no. 6,977,257 Claim 6 of Bristol-Myers Squibb s 257 patent recites: A pharmaceutical solution according to claim 1 wherein said pharmaceutically suitable solvent system is comprised of glycerin, propylene glycol and water each being present in ratios of : : w/w respectively. Claim 6 of the 257 patent is dependent on claim 1. Dependent claim 6 contains all the limitations of claim 1 on which it depends and also the limitation in claim 6; 35 U.S.C. 112, 4. Since Silarx Pharmaceuticals generic Aripiprazole Oral Solution drug product does not infringe claim 1 of the 257 patent, dependent claim 6 of the 257 patent is also not infringed literally or under the doctrine of equivalents by Silarx Pharmaceuticals generic Aripiprazole Oral Solution; Wahpeton Canvas Co. v. Frontier, Inc.; Jeneric/Pentron v. Dillon Co. and Chemichel, supra. Infringement analysis of claim 7 of Bristol-Myers Squibb s US patent no. 6,977,257 Claim 7 of Bristol-Myers Squibb s 257 patent recites: A pharmaceutical solution according to claim 1 wherein said pharmaceutically suitable solvent system is comprised of glycerin and water each being present in ratios of :: w/w respectively. Claim 7 of the 257 patent is dependent on claim 1. Dependent claim 7 contains all the limitations of claim 1 on which it depends and also the limitation in claim 7; 35 U.S.C. 112, 4. Since Silarx Pharmaceuticals generic Aripiprazole Oral Solution drug product does not infringe claim 1 of the 257 patent, dependent claim 7 of the 257 patent is also not infringed literally or under the doctrine of equivalents by Silarx Pharmaceuticals generic Aripiprazole Oral Solution; Wahpeton Canvas Co. v. Frontier, Inc.; Jeneric/Pentron v. Dillon Co. and Chemichel, supra. Infringement analysis of claim 8 of Bristol-Myers Squibb s US patent no. 6,977,257 Claim 8 of Bristol-Myers Squibb s 257 patent recites: A pharmaceutical solution according to claim 1 wherein said pharmaceutically suitable solvent system is comprised of glycerin and water each being present in ratios of about 1:3 w/w respectively. Claim 8 of the 257 patent is dependent on claim 1. Dependent claim 8 contains all the limitations of claim 1 on which it depends; 35 U.S.C. 112, 4. Since Silarx Pharmaceuticals generic Aripiprazole Oral Solution does not infringe claim 1 of the 257 patent, dependent claim 8 of the 257 patent is also not infringed literally or under the doctrine of equivalents by Silarx Pharmaceuticals generic Aripiprazole Oral Solution; Wahpeton Canvas Co. v. Frontier, Inc.; Jeneric/Pentron v. Dillon Co. and Chemichel, supra. Infringement analysis of claim 9 of Bristol-Myers Squibb s US patent no. 6,977,257 19

20 Case 3:12-cv MLC-LHG Document 23 Filed 02/05/13 Page 20 of 25 PageID: 360 Claim 9 of Bristol-Myers Squibb s 257 patent recites: A pharmaceutical solution according to claim 1 further comprising disodium EDTA. Claim 9 of the 257 patent is dependent on claim 1. Dependent claim 8 contains all the limitations of claim 1 on which it depends and also the limitation in claim 8; 35 U.S.C. 112, 4. Since Silarx Pharmaceuticals generic Aripiprazole Oral Solution drug product does not infringe claim 1 of the 257 patent, dependent claim 9 of the 257 patent is also not infringed literally or under the doctrine of equivalents by Silarx Pharmaceuticals generic Aripiprazole Oral Solution; Wahpeton Canvas Co. v. Frontier, Inc.; Jeneric/Pentron v. Dillon Co. and Chemichel, supra. Infringement analysis of claim 10 of Bristol-Myers Squibb s US patent no. 6,977,257 Claim 10 of Bristol-Myers Squibb s 257 patent recites: A pharmaceutical solution suitable for oral administration comprising aripiprazole, a pharmaceutically suitable solvent system, one or more taste enhancing/masking agents and lactic acid, wherein said solution has ph from 2.5 to 4.5. Claim 10 of Bristol-Myers Squibb 257 patent recites 4 elements: 1) A pharmaceutical solution suitable for oral administration comprising aripiprazole, 2) a pharmaceutically suitable solvent system, 3) one or more taste enhancing/masking agents and lactic acid, 4) wherein said solution has ph from 2.5 to 4.5. The claim comparison chart for claim 10 of Bristol-Myers Squibb s 257 patent versus Silarx Pharmaceuticals generic Aripiprazole Oral Solution is tabulated below: Bristol-Myers Squibb s 257 patent, claim 10 A pharmaceutical solution suitable for oral administration comprising aripiprazole Active: aripiprazole Solvent system: a pharmaceutically suitable solvent system one or more taste enhancing /masking agents ph adjustment: and lactic acid Silarx Pharmaceuticals generic Aripiprazole Oral Solution composition Aripiprazole Water, propylene glycol PFC 9620 orange flavor and sucralose Phosphoric acid Not Found In Silarx s generic Aripiprazole Oral Solution: lactic acid either literally or under the doctrine of equivalents ph range of drug product solution: wherein said 5.0 to

21 Case 3:12-cv MLC-LHG Document 23 Filed 02/05/13 Page 21 of 25 PageID: 361 solution has a ph from 2.5 to 4.5 Not Found In Silarx s generic Aripiprazole Oral Solution: ph from , either literally or under the doctrine of equivalents The lactic acid limitation in claim 10 is not found in Silarx Pharmaceuticals Aripiprazole Oral Solution. Accordingly, claim 10 is not literally infringed by Silarx Pharmaceutical s Aripiprazole Oral Solution. Also, the lactic acid limitation in claim 10 is not infringed by Silarx Pharmaceuticals Aripiprazole Oral Solution under the doctrine of equivalents because the phosphoric acid used to adjust the ph of Silarx Pharmaceuticals generic Aripiprazole Oral Solution does not perform substantially the same function in substantially the same way to obtain the same result as the lactic acid recited in claim 10 (see discussion at pages 5-6 and 9, herein). Graver Tank, supra. Furthermore, the fourth limitation wherein the solution has a ph from 2.5 to 4.5 in claim 10 of Bristol-Myers Squibb s 257 patent is not found in Silarx Pharmaceutical s generic Aripiprazole Oral Solution which has a ph in the range. Accordingly, claim 10 of Bristol-Myers Squibb s 257 patent is not literally infringed by Silarx Pharmaceuticals Aripiprazole Oral Solution. Southwall Technologies, supra. Furthermore, Silarx Pharmaceutical s Aripiprazole Oral Solution does not infringe the limitation wherein the solution has a ph from 2.5 to 4.5 in claim 10 of Bristol-Myers Squibb s 257 patent under the doctrine of equivalents for the following reasons. The function of the 2.5 to 4.5 ph range in claim 10 is to maintain the pharmaceutical solution at a high to moderate acidic state. In contrast the function of the ph range in Silarx Pharmaceuticals Aripiprazole Oral Solution is to maintain the solution at a slightly acidic, buffering state. Also, the way the pharmaceutical solution in claim 1 is adjusted to ph is distinguishable from the way the Silarx Pharmaceutical s Aripiprazole Oral Solution is adjusted to 5.0-5,8. The pharmaceutical solution in claim 10 is adjusted to a ph of by the use of organic acids from the group consisting of lactic acid, acetic acid, tartaric acid and citric acid; in contrast Silarx Pharmaceuticals Aripiprazole Oral Solution is adjusted to a ph of by an inorganic phosphoric acid. Furthermore, the result achieved by the two acids is different. Lactic acid provides a chelating action in claim 10; in contrast, phosphoric acid provides a buffering action in Silarx Pharmaceutical s Aripiprazole Oral Solution. Furthermore, the ph limitation of 2.5 to 4.5 in original claim 1 was narrowed during prosecution to 2.5 to 4.0. Accordingly, the Festo presumption of prosecution history estoppel applies to all claims including claim 10 containing that same ph limitation, regardless of whether claim 10 was or was not amended during prosecution. Deering Precision Instruments, LLC, supra. Accordingly, equivalents of ph of 2.5 to 4.0 are not available to Bristol-Myers Squibb. Also, there is no showing by Bristol-Myers Squibb that Silarx Pharmaceuticals equivalent of: 21

22 Case 3:12-cv MLC-LHG Document 23 Filed 02/05/13 Page 22 of 25 PageID: a generic pharmaceutical Aripiprazole Oral Solution with a ph of instead of the ph of recited in claim 10, and - use of phosphoric acid in Silarx Pharmaceuticals generic Aripiprazole Oral Solution in lieu of the lactic acid recited in claim 10 were unforeseeable at the time of the application; or, the rationale underlying the amendment bears no more than a tangential relation to the equivalent in question; or, there was some other reason that Bristol-Myers Squibb could not reasonably be expected to have described the insubstantial substitute in question. Therefore, equivalents of the following limitations in claim 10 are not available to Bristol Myers-Squibb: lactic acid and a ph of Accordingly, Silarx Pharmaceuticals use of: - phosphoric acid in their generic Aripiprazole Oral Solution does not infringe the lactic acid limitation in claim 10 of Bristol-Myers Squibb s 257 patent under the doctrine of equivalents, and - a pharmaceutical solution with a ph of in their generic Aripiprazole Oral Solution does not infringe the limitation wherein said solution has a ph from 2.5 to 4.5 in claim 10 of Bristol-Myers Squibb s 257 patent under the doctrine of equivalents. Festo, supra.; and Deering Precision Instruments, LLC, supra. Accordingly, for one or more of the reasons presented above, Silarx Pharmaceuticals Aripiprazole Oral Solution does not infringe claim 10 of Bristol-Myers Squibb s 257 patents either literally, or under the doctrine of equivalents. Infringement analysis of claim 11 of Bristol-Myers Squibb s US patent no. 6,977,257 Claim 11 of Bristol-Myers Squibb s 257 patent recites: A pharmaceutical solution according to claim 10 wherein said pharmaceutically suitable solvent system is comprised of one or more agents selected from the group consisting of water, ethanol, glycerin, propylene glycol and sorbitol and wherein said solution has a ph from 2.5 to 4.0. Claim 11 of the 257 patent is dependent on claim 10. Dependent claim 11 contains all the limitations of claim 10 on which it depends and also the limitation in claim 8; 35 U.S.C. 112, 4. Since Silarx Pharmaceuticals generic Aripiprazole Oral Solution does not infringe claim 10 of the 257 patent, dependent claim 11 of the 257 patent is also not infringed literally or under the doctrine of equivalents by Silarx Pharmaceuticals generic Aripiprazole Oral Solution; Wahpeton Canvas Co. v. Frontier, Inc.; Jeneric/Pentron v. Dillon Co. and Chemichel, supra. Infringement analysis of claim 12 of Bristol-Myers Squibb s US patent no. 6,977,257 Claim 12 of Bristol-Myers Squibb s 257 patent recites: A pharmaceutical solution according to claim 11 wherein one or more of said taste-enhancing/masking agents are 22