Please find below and/or attached an Office communication concerning this application or proceeding.

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1 UNITED STATES patent AND TRADEMARK OFFICE UNITED STATES DEPARTMENT OF COMMERCE United Statl.'.s Patent and Trademark Office Ad<lress: COMMISSIONER FOR PATENTS P.O. Dox 1450 Alexandda, Virginia APPI.JCATION NO. FILING DATE /14/2014 FIRST NAMED INVENTOR Jlcnrik NILSSON ATTORNEY DOCKET NO. CONFIRMATION NO CLARK & ELBING LLP 101 FEDERAL STREET BOSTON, MA /17nOIS EXAMlNER CHANNA VAJJALA. LAKSHMI SARADA ART UNIT PAPER!\'UMBER NOTIFICATION DA'lll DELIVERY MODE 04117/2015 ELECTRONIC Please find below and/or attached an Office communication concerning this application or proceeding. The time peliod for reply, if any, is set in the attached communication. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the foljowing address(es): patentadministrator@clarkelbing.com PTOL-90A (Rev )

2 Office Action Summary Application No. 14/212,503 Examiner LAKSHMI CHANNAVAJJALA Applicant(s) NILSSON ET AL. Art Unit 1611 I AlA (First Inventor to File) Status No -- The MAILING DATE of this communication appears on the cover sheet with the correspondence address - Period for Reply A SHORTENED STATUTORY PERIOD FOR REPLY IS SET TO EXPIRE ;J MONTHS FROM THE MAILING DATE OF THIS COMMUNICATION. Extensions of time may be available under the provisions ol 37 CFR t.t36(a). In no event, however. may a reply be timely filed after SIX (6) MONTHS from the mailing date of this communication. If NO period for reply is specified above, the maximum statutory period will apply and will expire SIX (6) MONTHS from the mailing date of this communication. Failure to reply whhin the set or extended period for reply will, by statute, cause the application to become ABANDONED (35 U.S.C. 133). Any reply received by the O ffice later than three months alter the mailing date of this communication, even if timely tiled, may reduce any earned patent term adjustment. See 37 CFR (b). Status 1)~ Responsive to communication(s) filed on 12119/14. 0 A declaration(s)/affidavit(s) under 37 CFR 1.130(b) was/were filed on. 2a)~ This action is FINAL. 2b)0 This action is non-final. 3)0 An election was made by the applicant in response to a restriction requirement set forth during the interview on ; the restriction requirement and election have been incorporated into this action. 4)0 Since this application is in condition for allowance except for formal matters, prosecution as to the merits is closed in accordance with the practice under Ex parte Quayle, 1935 C. D. 11, 453 O.G Disposition of Claims* 5)181 Claim(s) is/are pending in the application. 5a) Of the above claim(s) is/are withdrawn from consideration. 6)0 Claim(s) is/are allowed. 7)[81 Claim(s) is/are rejected. 8)0 Claim(s) is/are objected to. 9)0 Claim(s) are subject to restriction and/or election requirement. If any claims have been determined allowable, you may be eligible to benefit from the Patent Prosecution Highway program at a participating intellectual property office for the corresponding application. For more information, please see events/pph/index.jsp or send an inquiry to PPHfeedbackCwuspto.gov. Application Papers 1 0)0 The specification is objected to by the Examiner. 11 )0 The drawing(s) filed on is/are: a)o accepted or b)o objected to by the Examiner. Applicant may not request that any objection to the drawing(s) be held in abeyance. See 37 CFR 1.85(a). Replacement drawing sheet(s) including the correction is required if the drawing(s) is objected to. See 37 CFR (d). Priority under 35 U.S.C ) 0 Acknowledgment is made of a claim for foreign priority under 35 U.S.C. 119(a)-(d) or (f). Certified copies: a)o All b)o Some** c)o None of the: 1.0 Certified copies of the priority documents have been received. 2.0 Certified copies of the priority documents have been received in Application No. 11/576, Copies of the certified copies of the priority documents have been received in this National Stage application from the International Bureau (PCT Rule 17.2(a)). See the attached detailed Office action for a list of the certified copies not received. Attachment(s) 1) 0 Notice of References Cited (PT0-892) 2)!8ltnfonnation Disclosure Statement(s) (PTO/SBIOSa and/or PTO/SB/OSb) Paper No(s)/Mall Date 12119/14: U.S. Patent and Ttademark 011/ce PTOL 326 (Rev ) Office Action Summary 3) 0 Interview Summary (PT0-413) Paper No(s)fMail Date.. 4) 0 Other:. Part ol Paper No./Mail Date

3 Page 2 1. The present application is being examined under the pre-ala first to invent provisions. DETAILED ACTION Receipt of amendment, response and I OS dated 12/19/14; and I OS 12/22/14 is acknowledged. Claim 1-45 have been canceled. Claims are pending in the instant application. In response to the amendment canceling claim 1 and the abandonment of some of the co pending applications. the following rejections have been withdrawn: Double Patenting 3. Claim 1 is provisionally rejected under 35 U.S.C. 101 as claiming the same invention as that of claim 1 of EACH copending Application Nos. 14/213,673; 14/213399; 14/209,756; 14/209,712; 14/209,651 and 14/209, Claims 1 and are provisionally rejected under 35 U.S.C. 101 as claiming the same invention as that of claims 1 and of copending Application No. 14/213, Claims 1 and are provisionally rejected under 35 U.S.C. 101 as claiming the same invention as that of claims 1-19 of copending Application No. 13/957,220.

4 Page 3 6. Claims 1 and are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-29 of copending Application No. 13/957, Claims 1 and are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6-14 and of copending Application No.13/957, Claim 1 is rejected under pre-ala 35 U.S.C. 102(b) as being anticipated by Joshi et al (US Patent 6,355,676) or Joshi et al 6,509,376 (all Joshi references disclose the same subject matter and therefore, Joshi patent is relied upon for explaining the teachings of both the references and described below) or anticipated by Speiser (US ). The following rejection of record has been maintained: 10. Claims 46-50, are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims of copending Application No. 11/576,871. Although the claims at issue are not identical, they are not patentably distinct from each other because both instant and the copending applications claim a method of treating multiple sclerosis by administrating an oral delayed release composition comprising dimethylfumarate in combination with pharmaceutical excipients such that a total daily dose of 480mg dimethylfumarate is administered per day. Both

5 Page4 sets of claims recite twice daily administration of administering dimethylfumarate in the form of tablet or capsule. While the copending claims do not recite the claimed plasma levels of monomethylfumarate, the compositions of both sets of claims recite the same amount of the active agent and therefore the claimed plasma levels are inherent to the composition of the claims of 11/576, Claims and are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims of copending Application No. 11/576,871 in view of in view of any one of US 7,320,999 to Joshi et al or US to Joshi et al. The copending claims discussed above are directed to a method of treating multiple sclerosis by administering an oral composition comprising 480 mg or 240 mg dimethylfumarate twice daily (new claim 63 of the copending application). The copending application does not recite the claimed excipients such as silica, talc, surfactant, carboxymethyl cellulose etc., microcrystals of the drug with the claimed particle sizes, and enteric coating of the same. Joshi ('992) teaches oral tablet formulations comprising fumaric acid derivatives, mono methyl and dimethyl fumarate, for treating auto-immune diseases such as multiple sclerosis (abstract and col. 1, I 66- col.2, I 52). The amount of fumaric acid esters is in the range of mg, which includes the claimed dose of 240 mg (see col. 3, I 15-19). Joshi teaches that the composition is in the form of pellets, micro-pellets, capsules,

6 Page 5 granulates etc. (col. 5, ) with a mean diameter of microns (col. 5, ). The composition of Joshi further comprises pharmaceutical excipients such as silicic acid, microcrystalline cellulose, magnesium stearate and kollidon (reads on surfactant) etc. (examples). Joshi teaches that the composition additionally contains enteric coating (example 1 in col. 6, I 9-29). Joshi '999 patent also teaches and claims a method of treating multiple sclerosis with an oral composition comprising dimethylfumarate in an amount ranging from mg (col. 4, ). Joshi '999 also teaches compositions similar to that of Joshi '992. Joshi patents do not suggest a dose of 240 mg of the instant claims. However, Joshi (both '999 and '992 patents) suggests active agent in an amount of mg, which includes the claimed 240 mg/dose. Therefore, it would have been obvious for one of an ordinary skill in the art at the time of the instant invention was made to prepare the compositions of the copending claims by employing microcrystals of drug in the particle sizes, and further coat the composition with an enteric coating polymer taught by Joshi references because a skilled artisan would have readily recognizes that dimethylfumarate containing oral compositions can be formulated in other ways, other than tablet and capsule form, such as those taught by Joshi references and still achieve an effective treatment to multiple sclerosis. While both Joshi patents fail to teach the claimed percentages of the excipients such as microcrystalline cellulose, magnesium stearate and silica, the said patents teaches all of the claimed excipients as being suitable in preparing an oral dosage form of dimethyl fumarate and suggests the said excipients in amounts as opposed to % weights. Hence, it would have been obvious for

7 Page 6 one of an ordinary skill in the art at the time of the instant invention was made to employ appropriate amounts of said excipients such as microcrystalline cellulose, magnesium stearate and silica etc., of Joshi in the dimethyl fumarate containing compositions of copending claims with an expectation to provide a tablet composition of appropriate strength and dissolution such that it provides the desired benefit i.e., treatment of multiple sclerosis. Joshi teaches administration of the composition comprising fumarate for a period of one week to several weeks. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Response to Arguments Applicant's arguments filed 12/19/14 have been fully considered but they are not persuasive. 12. Applicants argue that claims of 11/ do not recite "an oral delayed release composition" whereas instant claims are not limited to one type of delayed release but to any kind of delayed release, including the formulation of Fumaderm (see Kristensen Declaration date (12/20/11 ). Applicants argue that the claims of '871 application do not recite any particular pharmaceutical composition, whereas instant claims require a delayed release having a specified Cmax within a specified range. It is argued even if one considers separate administration of a 240 mg DMF, twice daily, according to the '871 application, the copending claims do not specify a delayed release dosage form, the claims may be practiced to deliver an immediate release allowing for a

8 Page 7 fast release and high Cmax, or allow for a slow release composition that allows a low Cmax compared to the Cmax for a delayed release composition. Accordingly, the instant provisional rejection fails to support this ground of rejection and should be withdrawn. Applicants further argue that if one employed a delayed release formulation containing 240 mg DMF, the excipients beneath the delayed release functionality, such as an ethyl cellulose coating, could slow the release of drug to produce a Cmax lower than the claimed 0.4 mg/l. Therefore, it is argued that the non-statutory double patenting rejection should be withdrawn. Applicants' arguments are considered but not found persuasive because while it is true that the claims should be interpreted in light of the specification but without importing the limitations from the specification, the copending claims recite the same total daily dose administered and further recite administering separate doses two times daily. When a certain total dose of a drug is given in two or more intervals, it is implicit that the release from the drug is delayed and that not the entire daily total dose is released at once (fast or immediately). With respect to "the functional limitation, Cmax of 0.4 to 2 mg/ml", as a practical matter, the Patent Office is not equipped to manufacture products by the myriad of processes put before it and then obtain prior art products and make physical comparisons therewith." In re Brown, 459 F.2d 531, 535, 173 USPQ 685, 688 (CCPA 1972). In this respect, the burden is on applicants to provide a comparison between the instant and copending claims. However, a mere allegation (without a comparative evidence) that the copending claims may or could slow the release of the active agent, or may be practiced only to slow the release, is not persuasive. Applicants

9 Page 8 have not shown why a skilled artisan would only prepare a slow release composition instead a delayed release and instead would only be able to prepare an immediate release dosage form from the claimed composition of 11 / Additionally, the rejection not only relies on the claims of 11/ alone but also on the secondary teachings of Joshi references for rejecting claims and 67-70, which teach the excipients that are also claimed in the instant invention. Hence, it would have been obvious for one of an ordinary skill in the art at the time of the instant invention was made to employ appropriate amounts of said excipients such as microcrystalline cellulose, magnesium stearate and silica etc., of Joshi in the dimethyl fumarate containing compositions of copending claims with an expectation to provide a tablet composition of appropriate strength and dissolution such that it provides the desired benefit i.e., treatment of multiple sclerosis. Joshi teaches administration of the composition comprising fumarate for a period of one week to several weeks. Hence, the rejection has been maintained. Conclusion THIS ACTION IS MADE FINAL Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a). A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any

10 Page 9 extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAKSHMI CHANNAVAJJALA whose telephone number is (571 ) The examiner can normally be reached on 9.00 AM PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Bethany Barham can be reached on The fax phone number for the organization where this application or proceeding is assigned is

11 Page 10 Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call (IN USA OR CANADA) or /LAKSHMI CHANNAVAJJALA/ Primary Examiner, Art Unit 1611