DETAILED ACTION
RESPONSE TO AMENDMENT
1. Receipt of Applicants’ amendments/remarks filed 3/26/2026 are acknowledged.
INFORMATION DISCLOSURE STATEMENT
2. No new Information Disclosure Statement has been submitted for review.
WITHDRAWN REJECTIONS
3. Rejections not reiterated from previous Office Actions are hereby withdrawn. The following rejections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Rejections- 35 USC § 103
4. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-16, 19, and 20-48 are rejected under 35 U.S.C. 103 as being unpatentable over Lorenz et al. (US 2014/0100256) and Clegg et al. “ARN-509: a novel anti-androgen for prostate cancer treatment”.
Lorenz et al. disclose androgen receptor singling inhibitor enzalutamide and disclose a solid dispersion and method for making such solid dispersion of enzalutamide (androgen receptor signaling inhibitor) (abstract 0016-0018 and 0107). Lorenz et al. teach that the composition can contain enzalutamide and an effective
0056-0057 0066, 0069 and 0073). Amorphous forms are taught (para 0020). Amorphous enzalutamide can exist with the solid amorphous dispersion as a pure phase e.g., solid solution of enzalutamide homogenously distributed throughout the polymer, or any combination of these states or states that lie intermediate between them (para 0032).Tablets are disclosed (para 0018). The formulations con contain 55-65 weight percent enzalutamide and HPMCAS can be in an amount of 60 % (i.e., inclusive of 1:1 ratio of drug to polymer) as well as having up to 3 times as much polymer to drug. (para 0091, 0159 and 0179). Lorenz et al. disclose tablet form of enzalutamide/polymer dispersion (para 0159 and 0179 and claims 1 and 3). Lorenz et al. disclose the polymer is not particularly limited, so long as enzalutamide can be carried as the solid dispersion. In some embodiments, the polymer is not particularly limited, so long as enzalutamide can be an amorphous state. Examples of the polymer include polyvinyl pyrrolidone (PVP), polyethyleneoxide (PEO), poly(vinyl pyrrolidone-co-vinyl acetate), polymethacrylates, polyoxyethylene alkyl ethers, polyoxyethylene castor oils, polycaprolactam, polylactic acid, polyglycolic acid, poly(lactic-glycolic) acid, lipids, cellulose, pullulan, dextran, maltodextrin, hyaluronic acid, polysialic acid, chondroitin sulfate, heparin, fucoidan, pentosan polysulfate, spirulan, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), carboxymethyl ethylcellulose (CMEC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), ethyl cellulose, cellulose acetate, cellulose butyrate, cellulose acetate butyrate, dextran polymer derivatives, and pharmaceutically acceptable forms, derivatives. In some embodiments, the polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS). In some embodiments, the polymers are hydroxypropyl methylcellulose acetate succinate (HPMCAS) and/or hydroxypropyl methyl cellulose (HPMC). These polymers may be added alone, or as mixtures thereof. In some embodiments, hydroxypropyl methylcellulose acetate succinate (HPMCAS) is hydroxypropylmethlycellulose acetate succinate M-grade (HPMCAS-M). Examples of hydroxypropylmethlycellulose acetate succinate M-grade include HPMCAS-MG (Shin-Etsu Chemical Co., Ltd.) (para 0073). Claim 3 recites polymethacrylates and the Examples recite polymethacrylate copolymers (i.e., Eudragit L100) (Ex. 9).
Lorenz et al. disclose .01 to 100 mg/kg of as suitable dosage (para 0025) and that enzalutamide is conveniently administered in unit dosage from containing 0.05 to 1000 mg or 5 to 1000 mg, 10 to 200 mg, or 40 to 160 mg of enzalutamide per unit dosage form (para 0026). Lorenz et al. discloses the enzalutamide/polymer dispersion contains less than 30 % of lipophilic microphase-forming materials (para 0071). The amount of concentration-enhancing polymer relative to the drug (enzalutamide) is 25 % by weight drug and 75 % by weight concentration-enhancing polymer (para 0089). Lorenz discloses that in some embodiments a tablet contains approximately 45-55 % of its total weight as 60 % A:HMPCAS-M dispersion, with the remainder inactive excipients including an disintegrant (para 0161). Lorenz discloses conventional matrix materials, complexing agents, solubilizers, fillers, disintegrating agents (disintegrants), or binders may be added as part of the composition itself or added by granulation via wet or mechanical or other means. These materials may comprise up to 90 wt % of the composition (para 0124). Examples of fillers include calcium hydrogen phosphate and magnesium stearate and examples of disintegrants include light anhydrous salicylic acid, crosspovidone, and croscarmellose sodium (para 0125-0128). Example 23 and Table 16, discloses solid dispersion is made up of about 38.8 % total weight of the composition which meets the claim and applicant has not demonstrated any evidence of criticality as Lorenz discloses the amount of the solid dispersion in the total composition can be varied. Lorenz et al. disclose spray drying and hot-melt extrusion and disclose solid particles (paras 0074, 0081, 0086, 0088, 0092-0094, 0097-0099, 0136, 0142, 0144). Lorenz disclose the drug and polymer are mixed and dissolved with solvent (para 0077). Enzalutamide conveniently administered in unit dosage form; for example, containing 0.05 to 10000 mg, 0.5 to 10000 mg, 5 to 1000 mg, 10 to 200 mg, or 40 to 160 mg of enzalutamide per unit dosage form (para 0026).
Lorenz et al. disclose AR antagonist enzalutamide but does not disclose ARN-509 (apalutamide).
Clegg et al. disclose that ARN-509 showed greater efficacy than MDV3100 (a.k.a. enzalutamide). Clegg et al. disclose that ARN-509 exhibits characteristics predicting a higher therapeutic index with a greater potential to reach maximally efficacious doses in man than current AR antagonists. ARN-509 is a promising therapeutic in both castration-sensitive and castration-resistant forms of cancer (abstract). It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to substitute one known androgen receptor antagonist (enzalutamide) for another (ARN-509). One would have been motivated to do so because both compounds are receptor antagonists used for the same purpose and substitution of one equivalent for another would have yielded predictable results.
Lorenz discloses that enzalutamide is an androgen receptor signaling inhibitor (antagonist) and is used as an agent for treating castration-resistant prostate cancer (paras 0004-0005). Clegg et al. discloses that enzalutamide is also an approved androgen receptor antagonist drug for metastatic castration resistant prostate cancer (intro). Both Lorenz (enzalutamide) and Clegg et al. (ARN-509) disclose anti androgen receptor antagonists for the treatment of castration-resistant prostate cancer. Substitution of one known compound for another is obvious absent any evidence to the contrary, and Clegg et al. discloses motivation to select as the androgen receptor antagonist ARN-509 such that it has a higher therapeutic index however, both have been approved as suitable androgen receptor antagonists as therapies for metastatic castration resistant prostate cancer. Thus, the combined teachings of Lorenz et al. and Clegg et al. clearly discloses that such compounds are functional equivalents and substitution of one known androgen receptor antagonist for another would obtain predicable results.
5. Claims 1, 8 and 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over Lorenz et al. (US 2014/0100256) and Clegg et al. “ARN-509: a novel anti-androgen for prostate cancer treatment” as applied to claims 1-16, 19 and 20-48 and further in view of Kulkarni et al. (WO 2005055987).
Lorenz et al. in view of Clegg has been discussed supra and disclose spray drying with a solvent, and it discloses methanol, however it does not specifically disclose a 1:1 mixture of dichloromethane and methanol. Kulkarni et al. discloses the preparation of a pharmaceutical dispersion which may use Eudragit L 100-55 as its polymer matrix material. Kulkarni discloses in its claims a 1:1 mixture of dichloromethane and methanol for use as a solvent in its spray drying process to make these dispersions. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to use the solvent mixture of Kulkarni in the spray dry process of Lorenz because Kulkarni et al. teaches that this is a suitable solvent mixture for preparing poly(meth)acrylate pharmaceutical solid dispersions. One would have had a reasonable expectation of success because both Lorenz and Kulkarni et al. are drawn to spray drying with solvent mixtures for preparing solid dispersion using poly(methacrylate) polymers.
6. Claims 1, 5-10,12,14-16 and 20-48 are rejected under 35 U.S.C. 103 as being unpatentable over Njar (US Patent 9387216) as evidenced by Thakral et al. “Eudragit: a technology evaluation” and in view of Lorenz et al. (US 2014/0100256) and Clegg et al. “ARN-509: a novel anti-androgen for prostate cancer treatment”.
Njar (US Patent 9387216) (hereinafter Njar.) discloses pharmaceutical formulations for the delivery of ARN-509, and it also discloses that its formulations may take the form of a solid dispersion which also includes a poly(meth)acrylates such as Eudragit polymers (col. 29, lines 56-66, col 20, lines 26-50, col. 30 lines 38-67). Eudragit polymers are copolymers, as is disclosed in the Thakral et al. evidentiary reference. Njar does not disclose the Eudragit and ARN-509 together in one embodiment, however Njar discloses that compound of formula I can be used in combination with anti-androgen therapy compounds which include ARN-509. Njar states, “the solid dispersion of the compound in matrix can be prepared by forming a homogeneous solution or melt of the drug and polymer, followed by solidifying the mixture” (i.e. a solid solution). Njar discloses that the dispersion may be made by spray drying (i.e., amorphous) with solvent. Njar discloses that particles are created by a spray drying technique. Njar discloses pharmaceutical carriers. Njar discloses an oral tablet.
Njar and Thakral et al. do not disclose the weight of the solid dispersion ranges from 20 to 40 wt % total weight of the formulation.
Lorenz et al. (US 2014/0100256) (hereinafter Lorenz et al.) disclose androgen receptor singling inhibitor enzalutamide and disclose a solid dispersion and method for making such solid dispersion of enzalutamide (androgen receptor signaling inhibitor) (abstract 0016-0018 and 0107). Lorenz et al. teach that the composition can contain enzalutamide and an effective concentration of polymers that include polymethacrylate copolymer (para 0028-0031, 0056-0057 0066 and 0073). Amorphous forms are taught (para 0020). Tablets are disclosed (para 0018). The formulations con contain 55-65 weight percent enzalutamide and HPMCAS can be in an amount of 60 % (i.e., inclusive of 1:1 ratio of drug to polymer) as well as having up to 3 times as much polymer to drug. (para 0091, 0159 and 0179). Lorenz et al. disclose .01 to 100 mg/kg of as suitable dosage (para 0025) and that enzalutamide is conveniently administered in unit dosage from containing 0.05 to 1000 mg or 5 to 1000 mg, 10 to 200 mg, or 40 to 160 mg of enzalutamide per unit dosage form (para 0026). Lorenz et al. discloses the enzalutamide/polymer dispersion contains less than 30 % of lipophilic microphase-forming materials (para 0071). The amount of concentration-enhancing polymer relative to the drug (enzalutamide) is 25 % by weight drug and 75 % by weight concentration-enhancing polymer (para 0089). Lorenz discloses that in some embodiments a tablet contains approximately 45-55 % of its total weight as 60 % A:HMPCAS-M dispersion, with the remainder inactive excipients including a disintegrant (para 0161). Lorenz discloses conventional matrix materials, complexing agents, solublizers, fillers, disintegrating agents (disintegrants), or binders may be added as part of the composition itself or added by granulation via wet or mechanical or other means. These materials may comprise up to 90 wt % of the composition (para 0124). Examples of fillers include calcium hydrogen phosphate and magnesium stearate and examples of disintegrants include light anhydrous salicylic acid, crosspovidone, and croscarmellose sodium (para 0125-0128). Example 23 of Table 16 discloses solid dispersion is made up of about 38.8 % total weight of the composition which meets the claim and applicant has not demonstrated any evidence of criticality as Lorenz discloses the amount of the solid dispersion in the total composition can be varied.
Lorenz et al. does not disclose ARN-509. Clegg et al. “ARN-509: a novel anti-androgen for prostate cancer treatment” (hereinafter Clegg et al.) disclose that ARN-509 showed greater efficacy than MDV3100 (a.k.a. enzalutamide). Clegg et al. disclose that ARN-509 exhibits characteristics predicting a higher therapeutic index with a greater potential to reach maximally efficacious doses in man than current androgen receptor (AR) antagonists. ARN-509 is a promising therapeutic in both castration-sensitive and castration-resistant forms of cancer (abstract).
As such it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to substitute one known androgen receptor antagonist (enzalutamide) for another (ARN-509). One would have been motivated to do so because both compounds are receptor antagonists used for the same purpose and substitution of one equivalent for another would have yielded predictable results.
Lorenz discloses that enzalutamide is an androgen receptor signaling inhibitor (antagonist) and is used as an agent for treating castration-resistant prostate cancer (paras 0004-0005). Clegg discloses ARN-509 is also an androgen receptor antagonist for the treatment of castration-resistant prostate cancer (abstract). ARN-509 showed greater efficacy than MDV3100. This provides motivation to select ARN-509 as the preferred androgen receptor antagonist of choice. Clegg et al. discloses that enzalutamide is also an androgen receptor antagonist drug for metastatic castration resistant prostate cancer. Both Lorenz et al. (enzalutamide) and Clegg et al. (ARN-509) disclose anti androgen receptor antagonists for the treatment of castration-resistant prostate cancer. Substitution of one known compound for another is obvious absent any evidence to the contrary. Additionally Njar recognizes them as both choices suitable for use as the drug of choice in the anti- androgen therapy and Clegg et al. discloses motivation to select as the androgen receptor antagonist ARN-509 such that it has a higher therapeutic index however, both have been approved as suitable androgen receptor antagonists as therapies for metastatic castration resistant prostate cancer. Thus, the combined teaches of Njar et al., Lorenz et al., and Clegg et al. clearly discloses that such compounds are functional equivalents and substitution of one known androgen receptor antagonist for another would obtain predicable results.
7. Claims 1, 6, 8, 10-16 and 20-48 are rejected under 35 U.S.C. 103 as being unpatentable over Njar (US Patent 9387216) as evidenced by Thakral et al. “Eudragit: a technology evaluation”.
Njar (US Patent 9387216) (hereinafter Njar) discloses pharmaceutical formulations for the delivery of ARN-509, and it also discloses that its formulations may take the form of a solid dispersion which also includes a poly(meth)acrylates such as Eudragit polymers. Eudragit polymers are copolymers, as is disclosed in the Thakral et al. evidentiary reference.
Njar does not disclose the Eudragit and ARN-509 together in one embodiment, however its disclosure which explicitly says they can be used together to make a solid pharmaceutical dispersion and thus it would have been within the purview of the skilled artisan to use together. Njar states,“the solid dispersion of the compound in matrix can be prepared by forming a homogeneous solution or melt of the drug and polymer, followed by solidifying the mixture” (i.e. a solid solution). Njar discloses that the dispersion may be made by spray drying with solvent. Njar discloses that particles are created by a spray drying technique. Njar discloses pharmaceutical carriers. Njar discloses an oral tablet.
The specific combination of features claimed is disclosed within the broad generic ranges taught by the reference but such “picking and choosing” within several variables does not necessarily give rise to anticipation. Corning Glass Works v. Sumitomo Elec., 868 F.2d 1251, 1262 (Fed. Circ. 1989).
That being said, however, it must be remembered that “[w]hen a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious”. KSR v. Teleflex, 127 S,Ct. 1727, 1740 (2007) (quoting Sakraida v. A.G. Pro, 425 U.S. 273, 282 (1976)). “[W]hen the question is whether a patent claiming the combination of elements of prior art is obvious”, the relevant question is “whether the improvement is more than the predictable use of prior art elements according to their established functions.” (Id.). Addressing the issue of obviousness, the Supreme Court noted that the analysis under 35 USC 103 “need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ.” KSR v. Teleflex, 127 S.Ct. 1727, 1741 (2007). The Court emphasized that “[a] person of ordinary skill is… a person of ordinary creativity, not an automaton.” Id. at 1742.
Consistent with this reasoning, it would have obvious to have selected various combinations of various disclosed ingredients such a solid dispersion comprising ARN-509 with a polymethacrylate copolymer to arrive compositions yielding no more than one would expect from such an arrangement.
8. Claims 1 and 3-5 are rejected under 103 in view of Njar (US Patent 9387216) as evidenced by Thakral et al. “Eudragit: a technology evaluation”.
, as applied to claims 1, 6, 8, 10-16 and 20-48 above and further view of Huang et al. “Fundamental aspects of solid dispersion technology of poorly soluble drugs”.
Njar has been discussed supra. Njar does not disclose the specific ratios of the instant claims, and while it does contemplate amorphous drugs, it does not explicitly state that its ARN-509 is amorphous. Huang et al. “Fundamental aspects of solid dispersion technology of poorly soluble drugs” (hereinafter Huang et al.) is a reference which discusses solid pharmaceutical dispersions of a drug and a polymer generally. Huang et al. states, “the free drug concentration is dependent on the solubility of either amorphous or crystalline drug which in turn depends on the drug/polymer ratio, polymer dissolution rate and drug crystallization rate.” In light of this teaching, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention as filed to combine the teachings of Njar and Huang et al. , because Huang et al. teaches that the drug /polymer ratio of Njar is a result-effective variable. The result in this case is the free drug concentration. Result effective variable are obvious to optimize. Huang also states “the drug may form amorphous aggregates (Fig. 6B) and the free drug concentration in the dissolution media will be equal to the solubility of amorphous drugs. However, if the drug is present in a crystalline state in the solid dispersion particles (Fig. 6C), the free drug concentration in the solution decreases to that of the solubility of drug crystals, i.e., the dissolution advantage of the solid dispersion is lost.” This indicates that it is advantageous to have the drug in an amorphous form in such a solid dispersion because when it is not in amorphous form, “the dissolution advantage of the solid dispersion is lost.”
9. Claim 1 and 9 are rejected under 103 in view of Njar (US Patent 9387216) as evidenced by Thakral et al. “Eudragit: a technology evaluation”, as applied to claims 1, 6, 8, 10-16 and 20-48 above and further view of Li “Interactions between drugs and polymers influencing hot melt extrusion”.
Njar has been discussed supra. While Njar discloses using a melt for the manufacture of its solid dispersions, it does not specifically disclose a hot melt extrusion process. Li discloses a hot melt extrusion process for making a solid dispersion, and it discloses that prostate cancer drugs are already processed this way. Li states, “hot melt extrusion (HME) has been applied to enhance solubility of poorly water-soluble drug by producing amorphous solid dispersion (ASD) with many advantages such as solvent free, low cost, continuous process and potential of automation.” It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to subject the melt of Njar to the hot melt extrusion process of Li. One would have been motivated to do so because of the stated advantages of that process (i.e. solvent free, low cost, continuous process and potential of automation.)
10. Claim 1, 8, 16, 17 and 18 are rejected under 103 in view of Njar (US Patent 9387216) as evidenced by Thakral et al. “Eudragit: a technology evaluation, as applied to claims 1, 6, 8, 10-16 and 20-48 above and further view of Kulkarni et al. (WO 2005055987).
Njar has been discussed supra. Njar discloses spray drying with a solvent, and it discloses methanol, however it does not specifically disclose a 1:1 mixture of dichloromethane and methanol. Kulkarni et al. (WO 2005055987) (hereinafter Kulkarni et al.) discloses the preparation of a pharmaceutical dispersion which may use Eudragit L 100-55 as its polymer matrix material. Kulkarni discloses in its claims a 1:1 mixture of dichloromethane and methanol for use as a solvent in its spray drying process to make these dispersions. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to use the solvent mixture of Kulkarni in the spray dry process of Njar. One would have been motivated to do so because Kulkarni et al. teaches that this is a suitable solvent mixture for preparing poly(meth)acrylate pharmaceutical solid dispersions. One would have had a reasonable expectation of success because both Njar et al. and Kulkami et al. are drawn to spray drying with solvent mixtures for preparing solid dispersion using poly(methacrylate) polymers.
DOUBLE PATENTING
11. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claim 1-48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-37 of US Patent 10285948. Although the claims at issue are not identical, they are not patentably distinct from each other because the only difference between the two solid dispersions is the carrier of the ‘948 patent additionally includes HPMCAS however as taught by Njar and Lorenz as discussed supra, this is a suitable carrier for use in solid dispersion so it would have been within the purview of the skilled artisan to select the desired polymer.
Claims 1-48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of US Patent 12303493. Although the claims at issue are not identical, they are not patentably distinct from each other because the only difference between the two solid dispersions is the carrier of the ‘188 application additionally includes HPMCAS however as taught by Njar and Lorenz as discussed supra, this is a suitable carrier for use in solid dispersion so it would have been within the purview of the skilled artisan to select the desired polymer. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
RESPONSE TO ARGUMENTS
12. Applicants’ arguments have been fully considered and are not persuasive for the reasons below.
Applicants argue that ARN-509 and enzalutamide have different properties and chemical structures and liphophilicity. Appellants argue that there is no evidence that a skilled person would have been able to predict whether ARN-508 could form a solid dispersion at all. Applicants argue that the evidence of record indications that the skilled person would not have been able to make any predictions regarding the utility of using ARN-509 in a solid dispersion. Applicants argue that Dr. Vereck confirms that a person of ordinary skill in developing pharmaceutical dosage forms would have appreciated that any differences in chemical structure could result in how the APIs behave in solid dispersion. The differences in ARN-509 and enzalutamide led to measurable differences in chemical properties including polarity and lipophilicity. Williams demonstrates that solid dispersions were recognized as being associated with a great many complexities with their use with many factors contributing to appropriate physical stability. The stability of a solid dispersion is also dictated by intrinsic crystallization tendencies of the drug. Therefore, a person of ordinary skill in the art would not expect that a solid dispersion of ARN-509 could be obtained or that it would be stable. Chavan demonstrates that those working in the field frequently decided to use polymers other than a polymethacrylate copolymer.
Applicants argue hindsight.
Applicants argue that the statements of Williams et al. echo Lorenz’s conclusion that the solubilization of a specific drug depends on its chemical structure and physical properties therefore, whether any particular polymer will solubilize a specific drug is not necessarily predictable.
Applicants argue that there is no reason to believe that the cited text in Lorenz would have led a person of ordinary skill to focus on poly(methacrylate) copolymer, even in context with enzalutamide. There is no evidence of record that they could have any expectation that they could successfully formulate a poly(meth)acrylate copolymer with a different drug such as ARN-509.
Applicants argue that the data of Wilson demonstrate that the polymer selection has unpredictable effects on the dissolution properties, aggregation and bioavailability of solid dispersions. The affidavit of Henrist and the Oat or Declartion filed 3.26.2026 are acknowelged but are not found persuasive for the reasons below in that
In response, the Examiner respectfully submits that the test for obviousness is not whether the structures are identical. An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In reFout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). Conclusory statements that results were "unexpected," unsupported by objective factual evidence, were considered but were not found to be of substantial evidentiary value). Although an affidavit or declaration which states only conclusions may have some probative value, such an affidavit or declaration may have little weight when considered in light of all the evidence of record in the application. In re Brandstadter, 484 F.2d 1395, 179 USPQ 286 (CCPA 1973). The objective evidence of nonobviousness is not sufficient to outweigh the evidence of obviousness. Newell Cos. v. Kenney Mfg. Co., 864 F.2d 757, 769, 9 USPQ2d 1417, 1427 (Fed. Cir. 1988). In the instant case, The evidence relied upon is that enzalutamide and the claimed drug differ in properties but one of ordinary skill in the art would expect there to be some differences between different drugs that does not negate the obviousness to substitute one drug for another.
Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986) (differences in sedative and anticholinergic effects between prior art and claimed antidepressants were not unexpected). The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992) (Applicant alleged unexpected results with regard to the claimed soybean plant, however there was no basis for judging the practical significance of data with regard to maturity date, flowering date, flower color, or height of the plant.). See also In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) and In re Eli Lilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) as discussed in MPEP § 716.02(c). Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious." Id. at 301, 213 USPQ at 536. Furthermore, "Obviousness does not require absolute predictability of success." Id. at 903, 7 USPQ2d at 1681.The rationale to support a conclusion that the claim would have been obvious is that "a person of ordinary skill has good reason to pursue the known options within his or her technical grasp.
“Obviousness does not require absolute predictability of success.” Id. at 903, 7 USPQ2d at 1681. Conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) (“To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’”); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) (“This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness.” (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that “the expectation of success need only be reasonable, not absolute”)).
In the instant case, the Applicant has not provided any evidence of unexpected results to rebut the showing of prima facie obviousness. Applicant has not provided any evidence that the properties differ to such an extent that the difference is really unexpected. Furthermore, Applicant is arguing limitations that are not claimed as the declaration states difference in chemical structure could alter the physical and chemical stability profile of the API in solid dispersions as well as its bioavailability however, the claims do not recite any specific bioavailability, dissolution rate and stability. Furthermore, claim 1 is not drawn to a specific type of polymer. A genus of polymers (i.e., any polymethacrylate copolymers) are recited.
Claim 3 recites polymethacrylates as part of the claimed invention and Example 9 discloses polymethacrylate copolymers for use (Eudragit L100®). These are preferred embodiments. The Examiner maintains the position that it is prima facie obvious to one of ordinary skill in the art to substitute one known anti androgen drug for treatment of metastatic castration resistant prostate cancer for another and one of ordinary skill in the art would be led to use ARN-509 in view of Clegg for the stated benefits, e.g., higher therapeutic index.
Applicants argue that Clegg does not mention solid dispersions of ARN-509 and uses animal subjects.
In response, this is not found persuasive because Lorenz disclose solid dispersions of enzalutamide and Clegg et al. disclose that ARN-509 has greater efficacy than enzalutamide.
Applicants argue that the specification teaches the problem underlying the present invention was the provision of a formulation of ARN-509 with improved stability and a long shelf life and also a formulation that will permit a reduced pill burden. Tables a and b and 1-3 provide supporting data for tablets comprising a solid dispersion of ARN-509 and Eudragit. Data for different storage conditions and multiple months are provided. Tablets prepared using the claimed dispersion provide a rapid release of at least 94% of ARN-509 after 30 minutes, even after storage under the indicated conditions (Table 4).
In response, the Examiner respectfully submits that the claims are not commensurate in scope as they do not recite storage stability or conditions or release profiles. Table 4 recites test conditions and results but it is also not clear what specific formulation was used, for example, if its example 3.1 or 3.2 for the results shown of table 4.
Applicant argues that the Stability report tested the physical and chemical stability of hot melt extruded powder compared to hot melt extruded solid dispersions of ARN-509 using alternative polymer carriers and that hot melt extruded powders (API/Eudragit L100-55 ½ and API/Eudgragit L-100-55 1/3) remained physically stable as the amorphous form after 1 month storage at all tested storage conditions and that other polymeric carriers showed extensive degradation after 14 days storage.
In response, this argument is noted however, claim 1 is not commensurate in scope as claim 1 recites any poly(meth)acrylate copolymer whereas Eudragit L-100-55 at ½ and 1/3 is a specific methacrylate in specific ratio which is not commensurate in scope with claim 1. It is suggested that applicants amend the ratio and the polymer into claim 1 to be commensurate in scope.
Applicants argue that the double patenting rejections are premature. In response, the Examiner respectfully submits that since no terminal disclaimer has been filed, the double patenting rejections have been maintained.
CONCLUSION
13. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 nonprovisional extension fee (37 CFR 1.17(a)) 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.
CORRESPONDENCE
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Danah Al-awadi whose telephone number is (571) 270-7668. The examiner can normally be reached on 9:00 am - 6:00 pm; M-F (EST).
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Robert A. Wax can be reached on (571) 272-0623. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DANAH AL-AWADI/Primary Examiner, Art Unit 1615
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