BASF SE

Patent Trials and Appeals Board

Feb 10, 2022

2021002729 (P.T.A.B. Feb. 10, 2022)

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. 15/751,889 02/12/2018 Heiko Alexander Schiffter 29827/78798 6102 4743 7590 02/10/2022 MARSHALL, GERSTEIN & BORUN LLP 233 SOUTH WACKER DRIVE 6300 WILLIS TOWER CHICAGO, IL 60606-6357 EXAMINER GREENE, IVAN A ART UNIT PAPER NUMBER 1619 NOTIFICATION DATE DELIVERY MODE 02/10/2022 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): mgbdocket@marshallip.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte HEIKO ALEXANDER SCHIFFTER, MAXIMILIAN ANGEL KASENDORF, KARL KOLTER, and FELICITAS GUTH Appeal 2021-002729 Application 15/751,889 Technology Center 1600 BEFORE DONALD E. ADAMS, JEFFREY N. FREDMAN, and JOHN E. SCHNEIDER, Administrative Patent Judges. SCHNEIDER, Administrative Patent Judge. DECISION ON APPEAL STATEMENT OF THE CASE Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the Examiner’s decision to reject claims 12-15.2 We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. 1 We use the word Appellant to refer to “applicant” as defined in 37 C.F.R. § 1.42(a). Appellant identifies the real party in interest as BASF SE. Appeal Br. 3. 2 Claims 1-11 are pending in the application but have been withdrawn from consideration. Final Act. 1. Appeal 2021-002729 Application 15/751,889 2 CLAIMED SUBJECT MATTER The invention relates to the use of water-soluble polymers based on N-vinylpyrrolidone and acrylic acid as pharmaceutical auxiliaries, particularly to improve the solubility of basic active ingredients sparingly soluble in water. Spec. 1. Claim 123, reproduced below, is illustrative of the claimed subject matter: 12. A dosage form comprising a water-soluble formulation of an active ingredient sparingly soluble in water and a polymer according to claim 1, wherein the formulation consists of a basic active ingredient, which in uncharged form or as the hydrochloride has a solubility of less than 0.1 % (m/m) in water, artificial intestinal juice, or gastric juice, and a water- soluble polymer having a solubility in water of greater than 10% (m/m) in a pH range of 1 to 13 and which is obtained by a free-radically initiated polymerization of a monomer mixture of i) 78 to 82% by weight N-vinylpyrrolidone and ii) 18 to 22% by weight acrylic acid, wherein the sum total of i) and ii) corresponds to 100% by weight. REFERENCES The prior art relied upon by the Examiner is: Name Reference Date Weuts, et al., Phase behavior analysis of solid dispersions of loperamide and two structurally related compounds with the polymers PVP-K30 and PVP-VA64, 22 Eur. J. Pharm. Sci. (2004) Derman et al., Poly(N-Vinyl-2-Pyrrolidone-co-acrylic Acid - Bovine Serum Albumin Complex Formation Studied by HPLC and UV/Vis Spectroscopy, 17 Rom. Biotech Letters 7408 (2012) Hemalatha et al., Reactivity Ratios of N-Vinylpyrrolidone-Acrylic Acid Copolymer, 4 Am. J. Polymer Sci. 16 (2014). 3 Claim 12 includes a reference to claim 1 which has been withdrawn from consideration. For purposes of this Appeal, we treat claim 12 as if the reference to claim1 were deleted. Appeal 2021-002729 Application 15/751,889 3 REJECTION The Examiner has rejected claims 12-15 under 35 U.S.C. § 103 as unpatentable over Hemalatha in view of Derman and Weuts. OPINION The issue with respect to this rejection is whether a preponderance of the evidence supports the Examiner’s conclusion that the subject matter of claims 12-15 would have been obvious to one of ordinary skill in the art at the time the invention was made over Hemalatha combined with Derman and Weuts. The Examiner finds Hemalatha teaches copolymer of N- vinylpyrrolidone (NVP)- acrylic acid (AA) including copolymers having a NVP:AA ratio of 80:20. Final Act. 6. The Examiner finds Hemalatha teaches the amide group of NVP has a high binding affinity for several small and large molecules and that by citing the Otgiri4 reference, Hemalatha suggests use of the polymers in drug delivery. Id. The Examiner finds Hemalatha teaches the NVP-AA copolymer is produced by free radical polymerization. Id. The Examiner finds Hemalatha does not teach combining the NVP- AA copolymer with a basic therapeutic agent such as loperamide or haloperidol. Id. The Examiner finds Derman teaches poly(N-vinyl-3-pyrrolidone-co- acrylic acid) as a complex with bovine serum albumin (BSA) to form water- soluble and water insoluble complexes. Id. at 7. The Examiner finds 4 Otgiri et al., Spectroscopic study of the interaction of coumarin anticoagulant with polyvinylpyrrolidone, 7 J. Pharm. Biomed. Anal. 929 (1989). Appeal 2021-002729 Application 15/751,889 4 Derman teaches “the BSA-P(VP-co-AA) complexes were formed by the electrostatic interaction between oppositely charged BSA and P(VP-co-AA) molecules depending on a variety of parameters including system pH and molar ratio of the BSA to the P(VP-co-AA).” Id. The Examiner finds Weuts teaches the solubility and dissolution of loperamide can be increased through the use of solid dispersants. Id. at 8. The Examiner finds Weuts teaches combining loperamide with a polyvinylpyrrolidone homopolymer or a polyvinylpyrrolidone-vinyl acetate copolymer. Id. at 9. The Examiner concludes: It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce a water-soluble copolymer of N- vinylpyrrolidone and acrylic acid, in accordance with the teachings of Hemalatha et al., and to utilize the same in a pharmaceutical dosage form, for drug delivery, as suggested by Hemalatha et al. (i.e. good biocompatibility, low cytotoxicity) and Derman et al., and further to utilize a small molecule drug such as loperamide in a solid dispersion (i.e. a solid solution), as suggested by Weuts et al. in order to increase the physiological dissolution and thus the oral bioavailability of the drug, as taught by Derman et al. Id. The Examiner continues: From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention as Hemalatha et al. teaches how N-vinylpyrrolidone - acrylic acid copolymers are produced using free radical polymerization. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by Appeal 2021-002729 Application 15/751,889 5 the references, especially in the absence of evidence to the contrary. Id. at 10. Appellant contends while Hemalatha teaches the preparation of N- vinylpyrrolidone/acrylic acid copolymers, Hemalatha does not teach any specific application for the copolymers. Appeal Br. 6. Appellant contends that while Derman teaches using a copolymer of N-vinylpyrrolidone and acrylic acid, the active ingredient used in BSA which is not a basic ingredient and is water soluble. Id. at 10. Appellant also contends Derman teaches increasing solubility by increasing the amount of BSA. Id. Appellant contends that the copolymer of Derman does not meet the limitation calling for 78 to 82% by weight N-vinylpyrrolidone and 18 to 22% by weight acrylic acid. Id. at 11. Appellant contends Weuts uses a different polymer that the one recited in the claims and does not suggest the use of N-vinylpyrrolidone- acrylic acid copolymers. Id. Appellant contends that rejection is based on the improper use of hindsight. Id. at 12. Appellant contends: The combination of references fails to remotely provide any apparent reason for a skilled person to somehow combine and modify the cited references in a way that leads to the claimed invention with any reasonable expectation of providing a formulation containing a specifically-claimed N- vinylpyrrolidone/acrylic acid copolymer and a sparingly water- soluble, basic active ingredient that is water-soluble. In fact, the steps required to arrive at the claimed invention, as set forth above, are not all logical. Id. at 16. Appellant contends: Simply stated, a person skilled in the art would have had no apparent reason or incentive to substitute the water-soluble Appeal 2021-002729 Application 15/751,889 6 BSA of Derman with a claimed sparingly water-soluble basic active ingredient for incorporation into an N-vinylpyrrolidone - acrylic acid copolymer with a reasonable expectation of providing a water-soluble formulation. The examiner has provided no reasoning or evidence as to why a person skilled in the art would have made such an illogical substitution with any reasonable expectation of successfully providing a water- soluble formulation. Id. at 17. 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 a prima facie showing that the subject matter of the claims would have been obvious over Hemalatha combined with Derman and Weuts to a person of ordinary skill in the art at the time the invention was made. Appellant has not produced evidence showing, or persuasively argued, that the Examiner’s determinations on obviousness are incorrect. Only those arguments made by Appellant 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 12 as representative; therefore, all claims fall with claim 12. We address Appellants’ arguments below. We begin by noting that Appellant’s initial arguments are directed at the individual teachings of the references and not the combined teachings of the references. See Appeal Br. 9-12. These arguments are unpersuasive. “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 & Appeal 2021-002729 Application 15/751,889 7 Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986). As discussed more fully below, the rejection is based on the combined teachings of the references. Appellant’s argument regarding hindsight is equally unpersuasive. “Any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper.” In re McLaughlin, 443 F.2d 1392, 1395 (CCPA 1971). In the present appeal, Appellant has not pointed to nor do we discern any knowledge gleaned only from the present disclosure. See Appeal Br. 12-17. Appellant contends: The combination of references fails to render the present claims obvious. Hemalatha merely discloses copolymers, fails to disclose the specifically claimed copolymers, and is totally silent with respect to incorporating any active ingredient. Derman is directed to water-soluble BSA, and the polymer of Derman is unacceptable for pharmaceutical ingredients. Therefore, the most that can be derived from this combination is to incorporate BSA into a polymer of Hemalatha. Weuts is directed to polymers different from those of Hemalatha, with no apparent reason to make the modifications required to arrive at the presently claimed invention. Appeal Br. 16. Appellant goes on to argue: a person skilled in the art would have had no apparent reason or incentive to substitute the water-soluble BSA of Derman with a claimed sparingly water-soluble basic active ingredient for incorporation into an N-vinylpyrrolidone - acrylic acid copolymer with a reasonable expectation of providing a water- soluble formulation. The examiner has provided no reasoning or evidence as to why a person skilled in the art would have made such an illogical substitution with any reasonable Appeal 2021-002729 Application 15/751,889 8 expectation of successfully providing a water-soluble formulation. Id. at 17. We have considered Appellant’s arguments and are not persuaded that the rejection is in error. The current claims call for a formulation which the Specification defines as: a physical mixture, which enables the administration as medicament and which improves bioavailability. Essentially, there are no strong intermolecular interactions between the water-soluble polymers and the basic active ingredients. “No strong intermolecular interactions” signifies that only weak interactions occur as interactions between the molecules such as van der Waals interactions, hydrogen bonding or complex bonding. Spec. 5. Thus, any combination of a medicament such as loperamide with a polymer that improves the solubility of the loperamide and avoids strong intermolecular interactions can be a formulation. Weuts teaches mixtures of loperamide and poly vinylpyrrolidone homopolymer and polyvinylpyrrolidone vinyl acetate copolymers. Weuts, Abst. Weuts teaches that the mixtures help maintain the loperamide in an amorphous state, thereby improving the solubility of the loperamide. Id. Weuts teaches loperamide does not form hydrogen bonds with the polymers. Id. at 385. Weuts goes on to state “The performed study showed that the existence of specific interactions between polymer and LMWC is not a requirement to obtain completely amorphous samples. Dispersions of loperamide with the carriers were all amorphous, whereas IR-spectroscopy and the phase diagrams pointed towards the absence of such interactions.” Id. One skilled in the art would understand from reading Weuts that Appeal 2021-002729 Application 15/751,889 9 vinylpyrrolidone polymers can be used with loperamide to improve the solubility of loperamide. Derman teaches: Polymeric materials based on poly(N-vinyl-2- pyrrolidone) (PVP) and its copolymers have found wide applications as hydrogels, membranes used in drug-delivery systems. Besides its low chemical toxicity and high solubility in water/organic solvents, PVP's ability to complex with different kind of substrates like dyes, surfactants and other polymers, have promoted its use as a protective colloid in pharmaceutical and cosmetics products. Derman, 7409. Derman teaches the use of N-vinylpyrrolidone-acrylic acid to alter the solubility of BSA teaches the use of the polymer the development of drug compositions. Id. Abst. We agree with the Examiner that one skilled in the art would have been motivated to use the N-vinylpyrrolidone-acrylic acid copolymer of Derman in the loperamide compositions of Weuts and would have has a reasonable expectation of success. See Ans. 10-12. Appellant contends that Hemalatha does not teach the copolymer recited in the claims. Appeal Br. 9. Specifically, Appellant argues that Hemalatha teaches “a copolymer containing 76.43% N-vinylpyrrolidone and 23.57% acrylic acid (Sample No. 3), and a copolymer containing 86.9% N- vinylpyrrolidone and 13.81 % acrylic acid (Sample No. 4).” Id. Appellant contends these polymers do not meet the limitation of claim 12. Id. This argument is unpersuasive. Claim 12 does not call for a copolymer comprising specific amounts of monomers but calls for a copolymer polymerized a monomer mixture of i) 78 to 82% by weight N- vinylpyrrolidone and ii) 18 to 22% by weight acrylic acid, wherein the sum total of i) and ii) corresponds to 100% by weight. Appeal Br. A-1 (Claims Appeal 2021-002729 Application 15/751,889 10 Appx.) Hemalatha teaches N-vinylpyrrolidone-acrylic acid copolymer made by polymerizing a monomer feed ratio of 20% (0.2) N-vinylpyrrolidone and 80% (0.8) acrylic acid. Hemalatha, 17. Thus, Hemalatha teaches a copolymer falling within the scope of the claims. Based on the foregoing we conclude that a preponderance of the evidence supports the Examiner’s conclusion that the subject matter of claims 12-15 would have been obvious to one of ordinary skill in the art at the time the invention was made over Hemalatha combined with Derman and Weuts. CONCLUSION The Examiner’s rejection of claims 12-15 under 35 U.S.C. § 103 as unpatentable over Hemalatha combined with Derman and Weuts is affirmed. DECISION SUMMARY In summary: Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 12−15 103 Hemalatha, Derman, Weuts 12−15 TIME PERIOD FOR RESPONSE No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). See 37 C.F.R. § 1.136(a)(1)(iv). AFFIRMED