Peter A. Virsik et al.Download PDFPatent Trials and Appeals BoardAug 20, 201913906155 - (D) (P.T.A.B. Aug. 20, 2019) Copy Citation UNITED STATES PATENT AND TRADEMARK OFFICE UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 13/906,155 05/30/2013 Peter A. Virsik P233022.US.02 (X-0182 R1) 6553 20786 7590 08/20/2019 KING & SPALDING 1180 PEACHTREE STREET , NE ATLANTA, GA 30309-3521 EXAMINER DECK, JASON A ART UNIT PAPER NUMBER 1627 NOTIFICATION DATE DELIVERY MODE 08/20/2019 ELECTRONIC Please find below and/or attached an Office communication concerning this application or proceeding. The time period 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 following e-mail address(es): ATLIPDOCKETING@kslaw.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE __________ BEFORE THE PATENT TRIAL AND APPEAL BOARD __________ Ex parte PETER A. VIRSIK, DAVID J. WUSTOW, THAMIL ANNAMALAI, and SURESH K. MANTHATI __________ Appeal 2018-0020431 Application 13,906,155 Technology Center 1600 __________ Before DEBORAH KATZ, JOHN G. NEW, and JOHN E. SCHNEIDER, Administrative Patent Judges. SCHNEIDER, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134(a) from the Examiner’s rejection of claims to compounds for treating multiple sclerosis or psoriasis that have been rejected as obvious and for obviousness-type double patenting.2 We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. 1 Appellants identify Xenoport, Inc., as the real party in interest. Appeal Br. 3. 2 We have considered and herein refer to the Specification filed May 30, 2013 (“Spec.”); Final Office Action mailed Jan. 11, 2017 (“Final Act.”); Appeal Brief filed June 12, 2017 (“Appeal Br.”); Examiner’s Answer mailed Oct. 18, 2017 (“Ans.”); and Reply Brief filed Dec. 18, 2017 (“Reply Br.”). Appeal 2018-002043 Application 13/906,155 2 STATEMENT OF THE CASE Fumaric acid esters have been used to treat psoriasis for many years. Spec. ¶ 3. Oral administration of diemthyl fumarate has shown promising results in reducing symptoms of multiple sclerosis. Id. ¶ 8. Oral administration of these compounds often results in unwanted side effects such as serious digestive tract irritation with attendant nausea, vomiting, abdominal pain and diarrhea. Id. ¶¶ 7–8. The Specification discloses “improved methods of treating multiple sclerosis and/or psoriasis in human patients using fumaric acid esters. The methods are able to achieve high therapeutic levels of [methyl hydrogen fumarate] in the blood plasma of a patient without causing significant gastrointestinal irritation.” Id. ¶ 10. Claims 1, 2, 11, 14–18, 20–22, 32, 36, and 37 are on appeal.3 Claim 1 is the sole independent claim and reads as follows: 1. A method of treating multiple sclerosis in a human patient in need of such treatment, comprising orally administering to the patient a compound of (I): (I) or a pharmaceutically acceptable salt thereof, wherein: R1 and R2 are independently chosen from hydrogen, C1-6 alkyl, and substituted C1-6 alkyl; 3 Claims 4, 7, 10, 12, 25–31, and 33–35 are pending in the application but have been withdrawn from consideration. Final Act. 2. Appeal 2018-002043 Application 13/906,155 3 R3 and R4 are independently chosen from hydrogen, C1-6 alkyl, substituted C1-6 alkyl, C1-6 heteroalkyl, substituted C1-6 heteroalkyl, C4-12 cycloalkylalkyl, substituted C4-12 cycloalkylalkyl, C7-12 arylalkyl, and substituted C7-12 arylalkyl; or R3 and R4 together with the nitrogen to which they are bonded form a ring chosen from a C4-10 heteroaryl, substituted C4-10 heteroaryl, C4-10 heterocycloalkyl, and substituted C4-10 heterocycloalkyl; n is an integer from 0 to 4; and X is independently chosen from a single oxygen atom and a pair of hydrogen atoms; wherein each substituent group is independently chosen from halogen, -OH, -CN, -CF3 , =O, -NO2, benzyl, -C(O)NR112, -R11, -OR11, -C(O)R11, -COOR11, and -NR112 wherein each R11is independently chosen from hydrogen and C1-4 alkyl; and wherein when X is a single oxygen atom, the oxygen atom is connected to the carbon to which it is bonded by a double bond to form a carboxyl group and when X is a pair of hydrogen atoms, each hydrogen atom is connected to the carbon to which it is bonded to by single bond, said oral administration being sufficient to obtain (i) a therapeutic concentration of MHF in blood plasma of the patient of at least 0.5 μg/ml at a time within 24 hours after said oral administration; and (ii) an area under a concentration of MHF in blood plasma versus time curve (AUC) of at least 4.8 μg-hr/ml over 24 hours after start of the oral administration, and wherein a) the MHF prodrug exhibiting an average gastrointestinal irritation score in an Annamalai-Ma gastrointestinal irritation rat model of no more than 1.5 after orally administering a solution or suspension the prodrug to rats Appeal 2018-002043 Application 13/906,155 4 at a dose of 180 mg-equivalents of methyl hydrogen fumarate (MHF) per kg of body weight, dosed once per day over 4 consecutive days, or b) the MHF prodrug exhibits a relative GST enzyme activity (GSTArel) of less than 80%, where GSTArel is calculated in accordance with equation (I): GSTArel (%) = (SARprodrug ÷ SARDMF) x 100 (I) and SARprodrug is the specific activity ratio of the MHF prodrug, and SARDMF is the specific activity ratio of dimethyl fumarate, or both a) and b). The claims stand rejected as follows: Claims 1, 2, 11, 14–18, 20–22, 32, 36, and 37 have been rejected under 35 U.S.C. § 103(a) as unpatentable over Gangakhedkar,4 in view of Sagi.5 Claims 1, 2, 11, 14–18, 20–22, 32, 36, and 37 have been rejected for non-statutory obviousness-type double patenting over claims 19–29 of US 8,952,006 B2. Claims 20 and 21 have been rejected for non-statutory obviousness- type double patenting over claims 19–29 of US 8,952,006 B2 in view of Gangakhedkar. Claims 1, 2, 11, 14–18, 20–22, 32, 36, and 37 have been rejected for non-statutory obviousness-type double patenting over claims 19–29 of USS 13/973,700. 4 Gangakhedkar, et al, WO 2010/022177 A2; published Feb. 25, 2010 (“Gangakhedkar”). 5 Sagi et al., US 2005/0101779 A1; published May 12, 2005 (“Sagi”). Appeal 2018-002043 Application 13/906,155 5 DOUBLE PATENTING Appellants have offered no substantive argument regarding this rejection other than to ask that it be held in abeyance until allowable subject matter has been found in the present application. Appeal Br. 17–18. We therefore summarily affirm this rejection. 37 C.F.R. § 41.37(c)(iv). OBVIOUSNESS Issue The issue with respect to this rejection is whether a preponderance of the evidence supports the Examiner’s conclusion that the subject matter of the claims would have been obvious over Gangakhedkar combined with Sagi. The Examiner finds that Gangakhedkar teaches the administration of prodrugs of methyl hydrogen fumarate to treat multiple sclerosis. Final Act. 5. The Examiner finds that Gangakhedkar exemplifies fumarate prodrugs having the following structures: Id. at 6. The Examiner finds that Gangakhedkar teaches that the use of prodrugs results in “increased gastrointestinal permeability and absorption, improved solubility, and minimal cleavage in the gut lumen.” Id. at 5. The Examiner also finds that Gangakhedkar teaches the use of enteric coatings. Id. at 6. Appeal 2018-002043 Application 13/906,155 6 The Examiner finds that Sagi teaches a method for treating multiple sclerosis using prodrugs with carbonyl masking groups. Id. The Examiner finds that one of the masking groups used in Sagi is identical to one used in Gangakhedkar and several others, shown below, have high homology to the prodrug moieties used in Gangakhedkar. Final Act. 6 (citing Sagi 28–29). The Examiner concludes It would have been obvious to one of ordinary skill in the art at the time of filing of the instant invention to make and use methyl hydrogen fumarate prodrugs with the prodrug moieties of Sagi et al. and use them in the method of Gangakhedkar et al. with an enteric coating that inhibits release in the stomach. One of ordinary skill would have been motivated to make and use the instantly claimed compounds because Gangakhedkar et al. teaches that prodrugs of methyl hydrogen fumarate offer improved features over methyl hydrogen fumarate, and teaches the general type of prodrug moieties, while Sagi et al. discloses additional prodrug moieties for carboxylate groups that are of the same general type. The skilled artisan would have used the prodrug moieties of Sagi et al. for the method of Gangakhedkar et al. during the routine optimization of the properties of the compounds, and would have done so with a reasonable expectation of success in making an improved treatment for multiple sclerosis. One of ordinary skill would have been motivated to use the composition with an enteric coating that inhibits release in the stomach because these common formulations are well known to the skilled artisan, and Gangakhedkar et al. teaches Appeal 2018-002043 Application 13/906,155 7 that they are useful for the administration of MHF prodrugs in the treatment of multiple sclerosis. One skilled in the art would have used an enteric coating that inhibits release in the stomach for the MHF prodrug of Gangakhedkar et al. and Sagi et al. with a reasonable expectation of success in making an improved formulation for the treatment of multiple sclerosis. Final Act. 7. Principles of Law [T]he examiner bears the initial burden, on review of the prior art or on any other ground, of presenting a prima facie case of unpatentability. If that burden is met, the burden of coming forward with evidence or argument shifts to the applicant. After evidence or argument is submitted by the applicant in response, patentability is determined on the totality of the record, by a preponderance of evidence with due consideration to persuasiveness of argument. In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992). “[W]hen a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (citing United States v. Adams, 383 U.S. 39, 50–51 (1966)). Analysis We adopt the Examiner’s findings of fact, reasoning on scope and content of the prior art, and conclusions set out in the Final Action and Answer regarding this rejection. We find the Examiner has established that the subject matter of the claims would have been obvious to one of ordinary Appeal 2018-002043 Application 13/906,155 8 skill in the art at the time the invention was made over Gangakhedkar combined with Sagi. Appellants have not produced evidence showing, or persuasively argued, that the Examiner’s determinations on obviousness are incorrect. Only those arguments made by Appellants in the Briefs have been considered in this Decision. Arguments not presented in the Briefs are waived. See 37 C.F.R. § 41.37(c)(1)(iv) (2015). We have identified claim 1 as representative; therefore, all claims fall with claim 1. We address Appellants’ arguments below. Appellants contend that the references either alone or in combination do not teach or suggest the claimed compound. Appeal Br. 8. Appellants argue that the prodrugs disclosed in Gangakhedkar contain an additional carbonyl group at the carbon alpha to the nitrogen and Sagi is directed to prodrugs of phenylalanine derivatives and not methyl hydrogen fumarate. Id. Appellants argue that Sagi does not teach or suggest that the masking moieties disclosed therein can be used with other drug compositions. Id. at 9. Appellants also argue that even if one skilled in the art were motivated to use the prodrug moieties of Sagi with the fumarate of Gangakhedkar, it would not result in the claimed compound but would produce a compound with the following structure: Appeal 2018-002043 Application 13/906,155 9 See id. at 9. We have considered Appellants arguments and are not persuaded that the Examiner’s rejection is in error. Appellants’ arguments about the teachings of the individual references is not persuasive as it is the combined teachings of the references that serves as the basis for this rejection. “Non-obviousness cannot be established by attacking references individually where the rejection is based upon the teachings of a combination of references. [The reference] must be read, not in isolation, but for what it fairly teaches in combination with the prior art as a whole.” In re Merck & Co. Inc., 800 F.2d 1091, 1097 (Fed. Cir. 1986). Gangakhedkar teaches the preparation of prodrugs of methyl hydrogen fumarate and the benefits of such prodrugs. Gangakhedkar, 3–4. Both Gangakhedkar and Sagi teach the use of carboxyl masking groups including those which are structurally the same or similar. Compare, Gangakhedkar, 63 (example 3 and 65, example 9) with Sagi, 28–29 (Table A). It is prima facie obvious to substitute structurally similar compounds where there is evidence that the compounds share similar properties. In re Dillon, 919 F.2d 688, 691 (Fed. Cir. 1990). Given the teaching of the use of the same or structurally similar prodrug moieties, we find that one skilled in the art would have used the masking groups of Sagi for the compounds used in the method of Gangakhedkar. Appellants’ argument that the combination of Gangakhedkar and Sagi would result in a structure different from what is claimed is also not persuasive. Appellants offer no evidence, other than attorney argument, to support their contention that combining monomethyl fumarate with the prodrug moieties of Sagi would result in a peroxy-ester or per-ester. See, Appeal 2018-002043 Application 13/906,155 10 Appeal Br. 9. “Attorney’s argument in a brief cannot take the place of evidence.” In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974). As the Examiner points out, the teachings of Gangakhedkar and Sagi support the Examiner’s contention that the combination of the references would not lead to the peroxy ester or per-ester structure advanced by Appellants but would lead to the claimed structure. Ans. 14–19. Appellants argue that neither of the references teach or suggest the limitations regarding gastrointestinal irritation score, GST enzyme activity or blood plasma concentration after dosing. Appeal Br. 10. Appellants contend that the Examiner has improperly relied on inherency in that the Examiner has failed to demonstrate that these properties necessarily flow from the teachings of the art. Id. Appellants’ argument is unpersuasive. The Examiner has demonstrated that the combination of Gangakhedkar and Sagi would lead one skilled in the art to create compounds falling within the scope of the claims. As such one skilled in the art would expect the compounds to have the same properties are recited in the claims absent evidence to the contrary. In re Best, 562 F.2d 1252, 1255 (CCPA 1977). Here Appellants have advanced no persuasive evidence showing that the prior art compounds would not have the same properties as the claimed compounds. Appellants contend that one skilled in the art would not have been motivated to combine the teachings of Gangakhedkar and Sagi. Appeal Br. 11. Appellants contend that Gangakhedkar and Sagi teach the use of structurally dissimilar core compounds and that there is no teaching or suggestion in the references that would motivate one skilled in the art to combine the teachings of the references. Id. Appeal 2018-002043 Application 13/906,155 11 Appellants contend that nothing in either reference suggests that the disclosed prodrug moieties can be used for carboxylate groups generally and absent such a teaching, there would be no motivation to combine the references. Id. at 13. Appellants contend that Maag,6 cited by the Examiner does not suggest that varied core drugs can use the same of similar prodrug- moieties. Id. We have considered Appellants arguments and remain unpersauded that the rejection is in error. While we agree with Appellants that the core compounds of Gangakhedkar and Sagi are dissimilar, both sets of compounds are used to treat multiple sclerosis and both teach the use of prodrug moieties. Gangakhedkar, 4; Sagi ¶ 225. As the Examiner notes, both Gangakhedkar and Sagi teach the use of carboxylic acid prodrug moieties and the importance to optimize them. Ans. 28. As discussed above, Gangakhedkar and Sagi teach the use of the same or similar prodrug moieties. These teachings in the references would lead one skilled in the art to use the prodrug moieties of Sagi with the fumarate compounds of Gangakhedkar. Id. With respect to the teachings of Maag, while Maag teaches that only a few carboxylic acid drugs have been evaluated and marketed, we do not find that this teaches away from making the combination proposed by the Examiner. As the Examiner points out: It is well-known and understood that the number of compounds that fail on the way to market significantly outstrips the number of financially viable compounds. This is the reason that such a high level of experimentation is expected and reasonable within 6 Hans Maag, Prodrugs of Carboxylic Acids, in Prodrugs, Challenges and Rewards, Part 2 (Valention et al., eds., 2007) (“Maag”). Appeal 2018-002043 Application 13/906,155 12 the pharmaceutical arts. Further, both Gangakhedkar et al. and Sagi et al. disclose dozens of differing promoieties for their respective parent compounds, including overlapping moieties, showcasing that it was not only well-known in the pharmaceutical arts to try varied moieties to make prodrugs, it was also well-known in relation to multiple sclerosis treatments and was well-known with monomethyl fumarates. Ans. 26. Appellants contend that one skilled in the art would not have had a reasonable expectation of success in creating the claimed compound following the teachings of Gangakhedkar and Sagi. Appeal Br. 15. Appellants contend that given the structural dissimilarities of the drug cores of Gangakhedkar and Sagi and the lack of any teaching in Sagi that the prodrug moieties could be used with other drug cores, one skilled in the art would not expect the prodrug moieties of Sagi to work with the monomethyl fumarate of Gangakhedkar. Id. We are not persuaded by Appellants’ argument. “Obviousness does not require absolute predictability of success. . . . For obviousness under [section] 103, all that is required is a reasonable expectation of success.” In re O’Farrell, 853 F.2d 894, 903–04 (Fed. Cir. 1988). We agree with the Examiner that Gangakhedkar and Sagi teach the use of prodrug moieties to improve the effectiveness of carboxylic-acid- based drugs. Ans. 16. As discussed above, Gangakhedkar and Sagi teach the use of the same or structurally similar prodrug moieties. Compare, Gangakhedkar, 63 (examples 3, 9 and 65) with Sagi, 28–29 (Table A). From the discussion above, we find that the skilled artisan would have been aware of both the disclosures of Gangakhedkar et al. and Sagi et al., and would have been aware that carboxylate-prodrugs were useful and Appeal 2018-002043 Application 13/906,155 13 known. We also find that the skilled artisan would have been aware that the prodrug-moieties could be successfully substituted in the same drug-core, and that the prodrug-moieties could be successfully used in differing drug- cores. We agree with the Examiner that the skilled artisan would have combined the teachings of using of carboxylate-promoieties and would have done so with a reasonable expectation of success. Ans. 22. Conclusion of Law We conclude that a preponderance of the evidence supports the Examiner’s conclusion that the subject matter of claim 1 would have been obvious over Gangakhedkar combined with Sagi. Claims 2, 11, 14–18, 20–22, 32, 36, and 37 have not been argued separately and therefore fall with claim 1. See 37 C.F.R. § 41.37(c)(1)(iv). SUMMARY DECISION We affirm the rejection for non-statutory obviousness-type double patenting. We affirm the rejection under 35 U.S.C. § 103(a). No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). AFFIRMED Copy with citationCopy as parenthetical citation