DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
2. Claims 1-20 are currently pending in the instant application and are under examination.
Information Disclosure Statement
3. Applicant’s Information Disclosure Statement (IDS), submitted March 18, 2024, is in compliance with the provisions of 37 CFR 1.97. Accordingly the IDS has been considered by the examiner, please refer to the signed copy of Applicant’s PTO-1449 form, attached herewith.
Claim Rejections - 35 USC § 103
4. 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.
5. The factual inquiries 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.
6. This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
7. Claims 1-20 are rejected under 35 U.S.C. 103 as being obvious over Dalton, James, U.S. 8,110,562, in view of Yi, Ping, et al., Drug Metabolism and Disposition 2012, further in view of Chung et al., EP 2457892 A1 (all references cited on Applicant’s IDS of March 18, 2024).
Claim 1 is drawn to a method for increasing muscle mass, muscle strength, bone mass, or bone strength, or for increasing body lean muscle mass or reducing the increased body fat or body weight in a prostate cancer patient receiving androgen deprivation therapy,
comprising administering to a prostate cancer patient a pharmaceutical composition comprising a substantially pure form of (S)-(7- cyano-4-pyridin-2-ylmethyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)- carbamic acid isopropyl ester, or a pharmaceutically acceptable salt thereof, wherein said substantially pure compound is prepared by a process of reacting (S)-(7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid isopropyl ester and a 2-halomethylpyridine.
Claim 11 is drawn to a method for treating secondary hypogonadism induced by androgen deprivation therapy or the symptoms as a result of secondary hypogonadism induced by androgen deprivation therapy in a prostate cancer patient in need thereof, (wherein the symptoms are loss in bone mass, bone strength, muscle mass, muscle strength, loss of libido, and hot flashes (claim 20)),
comprising administering to a prostate cancer patient a pharmaceutical composition comprising a substantially pure form of (S)-(7-cyano-4-pyridin-2- ylmethyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid isopropyl ester, or a pharmaceutically acceptable salt thereof, wherein said substantially pure form of the compound is prepared by a process of (i) reacting (S)-(7-cyano- 1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid isopropyl ester and a 2-halomethylpyridine.
8. Dalton teaches the administration of compounds that are selective androgen receptor modulators (SARM), adjunct to ADT (androgen deprivation therapy) for the treatment of prostate cancer:
“In some embodiments, this invention provides for the use of a compound as herein described, or its prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrate or any combination thereof, for treating reducing the severity of, reducing the incidence of, or reducing pathogenesis of cancer. In another embodiment, the cancer comprises androgen AR dependent tumors (malignant or benign) such as prostate cancer, breast cancer (male or female, operable or inoperable). In another embodiment the SARM compounds adjunct to ADT for treating prostate cancer…”,
[emphasis added], (column 43, lines 8-19). Dalton discusses the symptoms of ADT:
“In one embodiment, the skeletal-related events are a result of cancer therapy. In one embodiment, the skeletal-related events are a result of hormone deprivation therapy, while in another embodiment they are a product of androgen deprivation therapy (ADT).
In one embodiment, the compounds of this invention are useful in prevention or reversal of androgen-deprivation therapy (ADT) induced side effects such as reduced muscle mass, reduced muscle strength, frailty, hypogonadism, osteoporosis, osteopenia, decreased BMD and/or decreased bone mass.”
[emphasis added] (column 37, lines 53-64). Dalton additionally teaches that said compound can be administered for increasing bone mass; increasing bone strength; increasing muscle strength; and enhancing libido; as well as reducing fat mass and/or increasing lean mass in a subject, (column 11, lines 23-24, and column 12, lines 6-15). Dalton teaches a pharmaceutical composition comprising said compound (column 7, lines 49-53).
9. As such, Dalton teaches a method of administering a pharmaceutical composition comprising a SARM compound to a subject with prostate cancer and having undergone androgen deprivation therapy (ADT), wherein said compound increases bone mass, increases bone strength; and increases muscle strength, but does not teach a method of administering (S)-(7-cyano-4-pyridin-2-ylmethyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid isopropyl ester.
10. Yet, Yi specifically teaches Applicant’s instantly recited SARM compound, “LY2452473” aka (S)-(7-cyano-4-pyridin-2-ylmethyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid isopropyl ester, which demonstrates potent androgen receptor specificity and is useful for treating disorders related to hypogonadism in men, (page 2354, left column, lines 2-5). Yi teaches that SARMS are known to demonstrate an increase in muscle mass and strength, and suggests the administration of LY2452473 for producing beneficial effects on bone and muscle mass and strength, (page 2354, left column, lines 9-10 and right column, last paragraph). As such, Yi suggests the administration of Applicant’s instantly recited compound: (S)-(7-cyano-4-pyridin-2-ylmethyl-1,2,3,4-tetrahydrocyclopenta-[b]indol-2-yl)-carbamic acid isopropyl ester to treat symptoms of hypogonadism, i.e. reduced bone mass, bone strength and reduced muscle mass or muscle strength.
11. Therefore it would have been obvious to one of skill in the art before the effective filing date of the claimed invention to administer the instantly recited SARM compound to increase muscle mass, muscle strength, bone mass, and bone strength in a patient suffering from prostate cancer and having undergone ADT, resulting in symptoms of a loss of bone mass, bone strength, muscle mass, and/or muscle strength. One skilled in the art looking to minimize the side effects resulting from secondary hypogonadism induced by ADT in a prostate cancer patient, i.e., reduced bone mass or density, reduced muscle mass or strength, would be motivated to employ the compound LY2452473, and would have a reasonable expectation of success.
12. Dalton does not teach the limitation of the “substantially pure form” of the compound recited in claims 11 and 11.
13. However, Chung et al. teach a process of purification giving rise to highly pure compounds, avoiding complicated purification procedures which ultimately lower the yield, and utilize safe, environmentally friendly and affordable reagents (paragraph [0038]). Chung et al. teach the benefits of preparing highly pure selective androgen receptor modulators (SARM) by recrystallizing from a mixture of a non-toxic organic solvent (such as ethanol) and water (paragraphs [0036]-[0039]). While purer forms of known products may be patentable, the purity of a product, by itself, does not render the product nonobvious. As the instantly recited composition comprises a purified form of an old product, (i.e., compound LY2452473 disclosed by Yi et al.) and that product has the same utility as the instantly recited compound (i.e., SARM), one skilled in the art before the effective filing date of the claimed invention would have recognized the desirability of purifying androgen receptor modulators in view of Chung et al. and would have been motivated to administer the instantly recited substantially pure form of S)-(7-cyano-4-pyridin-2-ylmethyl-1,2,3,4-tetrahydrocyclopenta-[b]indol-2-yl)-carbamic acid isopropyl ester to increase muscle mass, muscle strength, bone mass, and bone strength in a patient suffering from prostate cancer and having undergone ADT.
14. Regarding the recited method by which the substantially pure form of the compound is prepared in claims 1 and 11, Applicant is reminded that product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps (MPEP 2113). As stated by the court in In re Thorpe (777 F.2d 695 (Fed. Cir. 1985), "even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claims is the same or obvious from a product of the prior art, the claim is unpatentable even though the prior art product was made by a different process." As such, the claimed method by which the compound is produced does not carry patentable weight.
See also MPEP 2144.04 VII: if a first prior art process is improved to enhance the purity of the product produced by the process, and if the purified product has no structural or functional difference from the products produced by other prior art processes, then the improvement in the first process that improves the purity of the product does not give rise to patentability. See Purdue Pharma v. Epic Pharma, 811 F.3d 1345, 117 USPQ2d 1733 (Fed. Cir. 2016).
Thus, one skilled in the art before the effective filing date of the claimed invention would have been motivated to administer the instantly recited substantially pure form of S)-(7-cyano-4-pyridin-2-ylmethyl-1,2,3,4-tetrahydrocyclopenta-[b]indol-2-yl)-carbamic acid isopropyl ester, prepared by the recited method step, a patient suffering from prostate cancer and having undergone ADT, and would have reasonably expected an
increase in muscle mass, muscle strength, bone mass, and bone strength in said patient.
As such, claims 1, 11 and 20 are prima facie obvious.
Claim 2 is drawn to claim 1, wherein said process further comprises a step of (ii) recrystallizing the compound from ethanol.
Claim 12 is drawn to claim 11, wherein said process further comprises a step of (ii) recrystallizing the compound from ethanol.
15. Regarding the limitation of the recrystallizing, one skilled in the art would know that recrystallization of an isolate is commonly employed in order to produce a purer crystalline form of said isolate. If a known prior art process is improved to enhance the purity of the product produced by the process, and if the purified product has no structural or functional difference from the products produced by other prior art processes, then the improvement in the first process that improves the purity of the product does not give rise to patentability. See Purdue Pharma v. Epic Pharma, 811 F.3d 1345, 117 USPQ2d 1733 (Fed. Cir. 2016). See also MPEP § 2113.
16. Thus, one skilled in the art would be motivated to prepare a recrystallized form of compound LY2452473 disclosed by Yi et al., in order to obtain highly pure selective androgen receptor modulators in high yield, utilizing environmentally friendly reagents, with fewer purification steps, for administration to a prostate cancer patient receiving ADT and in need of an increase in muscle mass, muscle strength, bone mass, or bone strength.
As such, claims 2 and 12 are prima facie obvious.
Claim 3 is drawn to claim 1, wherein the process of preparation comprises the steps of:
(a) providing a solution of (S)-(7-cyano)-1,2,3,4-tetrahydro-cyclopenta[b]indol- 2-yl)carbamic acid isopropyl ester in DMF at about 40 0C; APPLICANT(S): Charles Thomas BILNSON ef al.SERIAL NO.:17/003,648FILED:August 26, 2020 Page 3(b) adding cesium carbonate to the solution to form a mixture; (c) adding 2-bromomethylpyridine hydrobromide portionwise to the mixture and stirring at 40 °C to provide a product in solution; (d) adding the product in solution to chilled water at 0 to 5 ˚C and stirring to form a solid; (e) isolating the solid by filtration and drying to provide the compound (S)-(7-cyano-4-pyridin-2-ylmethyl-1,2,3,4-tetrahydro- cyclopenta[b]-indol-2-yl)-carbamic acid isopropyl ester.
Claim 4 is drawn to claim 3, further comprising a step of purifying the compound by silica gel eluting with CH2Cl2/ EtOAc. Claim 5 is drawn to claim 3, further comprising a step of recrystallizing the compound from ethanol.
Claim 13 is drawn to claim 11, wherein the process of preparation comprises the steps of:
(a) providing a solution of (S)-(7-cyano)-1,2,3,4-tetrahydro-cyclopenta[b]indol- 2-yl)carbamic acid isopropyl ester in DMF at about 40 0C; APPLICANT(S): Charles Thomas BILNSON ef al.SERIAL NO.:17/003,648FILED:August 26, 2020 Page 3(b) adding cesium carbonate to the solution to form a mixture; (c) adding 2-bromomethylpyridine hydrobromide portionwise to the mixture and stirring at 40 °C to provide a product in solution; (d) adding the product in solution to chilled water at 0 to 5 ˚C and stirring to form a solid; (e) isolating the solid by filtration and drying to provide the compound (S)-(7-cyano-4-pyridin-2-ylmethyl-1,2,3,4-tetrahydro- cyclopenta[b]-indol-2-yl)-carbamic acid isopropyl ester.
Claim 14 is drawn to claim 13, further comprising a step of purifying the compound by silica gel eluting with CH2Cl2/ EtOAc. Claim 15 is drawn to claim 13, further comprising a step of recrystallizing the compound from ethanol.
17. Regarding the recited methods of preparing the compound in claims 3-5 and 13-15, Applicant is reminded that product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps (MPEP 2113). As stated by the court in In re Thorpe (777 F.2d 695 (Fed. Cir. 1985), "even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claims is the same or obvious from a product of the prior art, the claim is unpatentable even though the prior art product was made by a different process." As such, the claimed method by which the compound is produced does not carry patentable weight.
See also MPEP 2144.04 VII: if a first prior art process is improved to enhance the purity of the product produced by the process, and if the purified product has no structural or functional difference from the products produced by other prior art processes, then the improvement in the first process that improves the purity of the product does not give rise to patentability. See Purdue Pharma v. Epic Pharma, 811 F.3d 1345, 117 USPQ2d 1733 (Fed. Cir. 2016).
See also SmithKline Beecham Corp. v. Apotex Corp., No. 04-1522 (Fed. Cir. February 24, 2006), No. 04-1522 the federal circuit affirmed the grant of summary judgment that SmithKline Beckman's ("SKB's") `944 patent was invalid based on its own prior art `723 patent. SKB's `944 patent contained two product-by-process claims directed to the manufacture of a tableted form of paroxetine, a drug marketed as Paxil® used to treat depression. SKB's earlier `723 patent disclosed and claimed paroxetine in a pharmaceutically acceptable carrier. The district court relied on Scripps Clinic & Research Foundation v. Genentech, Inc., 927 F.2d 1565 (Fed. Cir. 1991) in giving the process limitations of the claims no patentable weight, and held the claims anticipated because the product claimed in the `944 patent was the same product disclosed in the `723 patent. The federal circuit affirmed, stating that "once a product is fully disclosed in the art, future claims to that same product are precluded, even if that product is claimed as made by a new process." Since the product was disclosed in the prior art `723 patent, it was immaterial whether the `944 patent's product-by-process claims were construed broadly to cover the product made by any process or narrowly to cover only the product made by a dry admixing process. Either way, anticipation by an earlier product disclosure (which disclosed the product itself) could not be avoided.
Accordingly, the derivation and/or production methods of the instantly recited compound are not further limiting.
18. Likewise, in claims 5 and 15, one skilled in the art would know that recrystallization of an isolate is commonly employed in order to produce a purer crystalline form of said isolate. If a known prior art process is improved to enhance the purity of the product produced by the process, and if the purified product has no structural or functional difference from the products produced by other prior art processes, then the improvement in the first process that improves the purity of the product does not give rise to patentability. See Purdue Pharma v. Epic Pharma, 811 F.3d 1345, 117 USPQ2d 1733 (Fed. Cir. 2016). See also MPEP § 2113.
19. Thus, one skilled in the art would be motivated to employ the recited SARM compound, prepared by the recited process, for administration to a prostate cancer patient receiving ADT and in need of an increase in muscle mass, muscle strength, bone mass, or bone strength.
As such, claims 3-5 and 13-15 are prima facie obvious.
Claim 9 is drawn to claim 1, and limits wherein said compound is administered orally or parenterally. Claim 10 is drawn to claim 1, and further limits wherein the composition is in the form of a capsule.
Claim 19 is drawn to claim 11, and limits wherein said compound is administered orally or parenterally.
20. Dalton additionally teaches that “…the pharmaceutical compositions are administered orally, and are thus formulated in a form suitable for oral administration, i.e. as a solid or a liquid preparation. … In one embodiment of the present invention, the SARM compounds are formulated in a capsule.” (column 20, lines 11-23).
21. Therefore one skilled in the art before the effective filing date of the claimed invention would have been motivated to orally administer a pharmaceutical composition comprising the instantly recited SARM compound in the form of a capsule, to a prostate cancer patient receiving ADT.
As such, claims 9, 10 and 19 are prima facie obvious.
Claim 6 is drawn to claim 1, and limits wherein said compound is administered at a dose of 1 mg-100 mg per day. Claim 7 is drawn to claim 1, and limits wherein said compound is administered at a dose of 1 mg, 5 mg, 25 mg, or 75 mg per day. Claim 8 is drawn to claim 11, and limits wherein said compound is administered at a dose of 5 mg per day.
Claim 16 is drawn to claim 11, and limits wherein said compound is administered at a dose of 1 mg-100 mg per day. Claim 17 is drawn to claim 11, and limits wherein said compound is administered at a dose of 1 mg, 5 mg, 25 mg, or 75 mg per day. Claim 18 is drawn to claim 11, and limits wherein said compound is administered at a dose of 5 mg per day.
22. Dalton additionally teaches dosage of said compound:
“the compound of this invention is administered at a dosage of 0.1-200 mg per day. In one embodiment, the compound of this invention is administered at a dose of 0.1-10 mg, or in another embodiment, 0.1-26 mg, or in another embodiment, 0.1-60 mg, or in another embodiment, 0.3-16 mg, or in another embodiment, 0.3-30 mg, or in another embodiment, 0.6-26 mg, or in another embodiment, 0.6-60 mg, or in another embodiment, 0.76-16 mg, or in another embodiment, 0.76-60 mg, or in another embodiment, 1-6 mg, or in another embodiment, 1-20 mg, or in another embodiment, 3-16 mg, or in another embodiment, 30-60 mg, or in another embodiment, 30-76 mg, or in another embodiment, 100-2000 mg… the compound of this invention is administered at a dosage of 1 mg. In another embodiment the compound of this invention is administered at a dosage of 3 mg, 6 mg, 10 mg, 16 mg, 20 mg, 26 mg, 30 mg, 36 mg, 40 mg, 46 mg, 50 mg, 56 mg, 60 mg, 66 mg, 70 mg, 76 mg, 80 mg, 86 mg, 90 mg, 96 mg or 100 mg,”
[emphasis added] (column 34, first two paragraphs), which fully embrace the dose of 1 mg-100 mg per day required by claims 6 and 16, the dosage of 1 mg, 5 mg, 25 mg, or 75 mg per day required by claims 7 and 17, and the dose of 5 mg per day required by claims 8 and 18.
23. Therefore one skilled in the art before the effective filing date of the claimed invention would have been motivated to administer a pharmaceutical composition comprising the instantly recited SARM compound at a dose of 1 mg-100 mg per day, a dose of 1 mg, 5 mg, 25 mg, or 75 mg per day, or a dose of 5 mg per day, to a prostate cancer patient receiving ADT.
As such, claims 6-8 and 16-18 are prima facie obvious.
Double Patenting
24. 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).
25. 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 § 2146 et seq. 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).
26. The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
27. The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
28. Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 10,758,515 B2, further in view of Chung et al., EP 2457892 A1.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are as follows:
Claim 1 is drawn to a method for increasing muscle mass, muscle strength, bone mass, or bone strength, or for increasing body lean muscle mass or reducing the increased body fat or body weight in a prostate cancer patient receiving androgen deprivation therapy,
comprising administering to a prostate cancer patient a pharmaceutical composition comprising a substantially pure form of (S)-(7- cyano-4-pyridin-2-ylmethyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)- carbamic acid isopropyl ester, or a pharmaceutically acceptable salt thereof, wherein said substantially pure compound is prepared by a process of reacting (S)-(7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid isopropyl ester and a 2-halomethylpyridine. Claim 2 is drawn to claim 1, wherein said process further comprises a step of (ii) recrystallizing the compound from ethanol. Claim 3 is drawn to claim 1, wherein the process of preparation comprises the steps of:
(a) providing a solution of (S)-(7-cyano)-1,2,3,4-tetrahydro-cyclopenta[b]indol- 2-yl)carbamic acid isopropyl ester in DMF at about 40 0C; APPLICANT(S): Charles Thomas BILNSON ef al.SERIAL NO.:17/003,648FILED:August 26, 2020 Page 3(b) adding cesium carbonate to the solution to form a mixture; (c) adding 2-bromomethylpyridine hydrobromide portionwise to the mixture and stirring at 40 °C to provide a product in solution; (d) adding the product in solution to chilled water at 0 to 5 ˚C and stirring to form a solid; (e) isolating the solid by filtration and drying to provide the compound (S)-(7-cyano-4-pyridin-2-ylmethyl-1,2,3,4-tetrahydro- cyclopenta[b]-indol-2-yl)-carbamic acid isopropyl ester.
Claim 4 is drawn to claim 3, further comprising a step of purifying the compound by silica gel eluting with CH2Cl2/ EtOAc. Claim 5 is drawn to claim 3, further comprising a step of recrystallizing the compound from ethanol.
Claim 6 is drawn to claim 1, and limits wherein said compound is administered at a dose of 1 mg-100 mg per day. Claim 7 is drawn to claim 1, and limits wherein said compound is administered at a dose of 1 mg, 5 mg, 25 mg, or 75 mg per day. Claim 8 is drawn to claim 11, and limits wherein said compound is administered at a dose of 5 mg per day. Claim 9 is drawn to claim 1, and limits wherein said compound is administered orally or parenterally. Claim 10 is drawn to claim 1, and further limits wherein the composition is in the form of a capsule.
Claim 11 is drawn to a method for treating secondary hypogonadism induced by androgen deprivation therapy or the symptoms as a result of secondary hypogonadism induced by androgen deprivation therapy in a prostate cancer patient in need thereof, (wherein the symptoms are loss in bone mass, bone strength, muscle mass, muscle strength, loss of libido, and hot flashes (claim 20)),
comprising administering to a prostate cancer patient a pharmaceutical composition comprising a substantially pure form of (S)-(7-cyano-4-pyridin-2- ylmethyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid isopropyl ester, or a pharmaceutically acceptable salt thereof, wherein said substantially pure form of the compound is prepared by a process of (i) reacting (S)-(7-cyano- 1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid isopropyl ester and a 2-halomethylpyridine.
Claim 12 is drawn to claim 11, wherein said process further comprises a step of (ii) recrystallizing the compound from ethanol. Claim 13 is drawn to claim 11, wherein the process of preparation comprises the steps of:
(a) providing a solution of (S)-(7-cyano)-1,2,3,4-tetrahydro-cyclopenta[b]indol- 2-yl)carbamic acid isopropyl ester in DMF at about 40 0C; APPLICANT(S): Charles Thomas BILNSON ef al.SERIAL NO.:17/003,648FILED:August 26, 2020 Page 3(b) adding cesium carbonate to the solution to form a mixture; (c) adding 2-bromomethylpyridine hydrobromide portionwise to the mixture and stirring at 40 °C to provide a product in solution; (d) adding the product in solution to chilled water at 0 to 5 ˚C and stirring to form a solid; (e) isolating the solid by filtration and drying to provide the compound (S)-(7-cyano-4-pyridin-2-ylmethyl-1,2,3,4-tetrahydro- cyclopenta[b]-indol-2-yl)-carbamic acid isopropyl ester.
Claim 14 is drawn to claim 13, further comprising a step of purifying the compound by silica gel eluting with CH2Cl2/ EtOAc. Claim 15 is drawn to claim 13, further comprising a step of recrystallizing the compound from ethanol.
Claim 16 is drawn to claim 11, and limits wherein said compound is administered at a dose of 1 mg-100 mg per day. Claim 17 is drawn to claim 11, and limits wherein said compound is administered at a dose of 1 mg, 5 mg, 25 mg, or 75 mg per day. Claim 18 is drawn to claim 11, and limits wherein said compound is administered at a dose of 5 mg per day. Claim 19 is drawn to claim 11, and limits wherein said compound is administered orally or parenterally.
29. The claims of U.S. Pat. No. 10,758,515 B2 recite the following:
1. A method of treating secondary hypogonadism induced by androgen deprivation therapy or the symptoms as a result of the secondary hypogonadism induced by androgen deprivation therapy in a prostate cancer patient in need thereof, comprising administering to the prostate cancer patient an effective amount of (S)-(7-cyano-4-pyridin-2-ylmethyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid isopropyl ester, or a pharmaceutically acceptable salt thereof, wherein no significant change in prostate specific antigen (PSA) occurs compared to a baseline level in said patient.
2. A method according to claim 1 wherein the symptoms are the loss in bone mass, bone strength, muscle mass, or muscle strength.
3. A method according to claim 1 wherein the symptoms are loss of libido and hot flashes.
30. Thus, the claims of U.S. Pat. No. 10,758,515 B2 recite the same method of administering Applicant’s instantly recited SARM compound, (S)-(7-cyano-4-pyridin-2-ylmethyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid isopropyl ester,
to a subject with prostate cancer and having undergone androgen deprivation therapy (ADT), resulting in symptoms of a loss of bone mass, bone strength, muscle mass, and/or muscle strength, but do not recite the substantially pure form of the compound or the process by which the compound is prepared.
31. However, Chunga et al. teach a process of purification giving rise to highly pure compounds, avoiding complicated purification procedures which ultimately lower the yield, and utilize safe, environmentally friendly and affordable reagents (paragraph [0038]). Chung et al. teach the benefits of preparing highly pure selective androgen receptor modulators (SARM) by recrystallizing from a mixture of a non-toxic organic solvent (such as ethanol) and water (paragraphs [0036]-[0039]). While purer forms of known products may be patentable, the purity of a product, by itself, does not render the product nonobvious. As the instantly recited composition comprises a purified form of the same product recited in U.S. Pat. No. 10,758,515, and that product has the same utility as the instantly recited compound (i.e., SARM), one skilled in the art would have recognized the desirability of purifying androgen receptor modulators in view of Chung et al. and would have been motivated to administer the instantly recited substantially pure form of S)-(7-cyano-4-pyridin-2-ylmethyl-1,2,3,4-tetrahydrocyclopenta-[b]indol-2-yl)-carbamic acid isopropyl ester to treat symptoms of muscle mass loss, muscle strength loss, bone mass loss, and bone strength loss in a patient suffering from prostate cancer and having undergone ADT.
32. Regarding the recited method by which the substantially pure form of the compound is prepared in claims 1 and 11, Applicant is reminded that product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps (MPEP 2113). As stated by the court in In re Thorpe (777 F.2d 695 (Fed. Cir. 1985), "even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claims is the same or obvious from a product of the prior art, the claim is unpatentable even though the prior art product was made by a different process." As such, the claimed method by which the compound is produced does not carry patentable weight.
See also MPEP 2144.04 VII: if a first prior art process is improved to enhance the purity of the product produced by the process, and if the purified product has no structural or functional difference from the products produced by other prior art processes, then the improvement in the first process that improves the purity of the product does not give rise to patentability. See Purdue Pharma v. Epic Pharma, 811 F.3d 1345, 117 USPQ2d 1733 (Fed. Cir. 2016).
33. Regarding the limitation of the recrystallizing, one skilled in the art would know that recrystallization of an isolate is commonly employed in order to produce a purer crystalline form of said isolate. If a known prior art process is improved to enhance the purity of the product produced by the process, and if the purified product has no structural or functional difference from the products produced by other prior art processes, then the improvement in the first process that improves the purity of the product does not give rise to patentability. See Purdue Pharma v. Epic Pharma, 811 F.3d 1345, 117 USPQ2d 1733 (Fed. Cir. 2016). See also MPEP § 2113.
34. Thus, one skilled in the art would have been motivated to practice the method recited by U.S. Pat No. 10,758,515 and administer the same SARM compound, (S)-(7-cyano-4-pyridin-2-ylmethyl-1,2,3,4-tetrahydrocyclopenta-[b]indol-2-yl)-carbamic acid isopropyl ester, in a substantially pure form, and prepared by the recited method step, to a patient suffering from prostate cancer and having undergone ADT, to treat to treat symptoms of muscle mass loss, muscle strength loss, bone mass loss, and bone strength loss (i.e., symptoms of secondary hypogonadism), and would have reasonably expected an increase in muscle mass, muscle strength, bone mass, and bone strength in said patient.
35. Regarding the recited dose amounts and route of administration, dose regimen optimization is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize given the guidance of the prior art. And, optimization of parameters such as route and form of administration is a routine practice that would be obvious for a person of ordinary skill in the art to employ. Thus it would been obvious to one of skill in the art to practice the method recited by U.S. Pat No. 10,758,515 and orally administer the same SARM compound, (S)-(7-cyano-4-pyridin-2-ylmethyl-1,2,3,4-tetrahydrocyclopenta-[b]indol-2-yl)-carbamic acid isopropyl ester, in a substantially pure form, and prepared by the recited method step, to a patient suffering from prostate cancer and having undergone ADT, to treat to treat symptoms of muscle mass loss, muscle strength loss, bone mass loss, and bone strength loss (i.e., symptoms of secondary hypogonadism), in the dose amounts recited.
As such, claims 1-20 are prima facie obvious over claims 1-4 of U.S. Pat. No. 10,758,515 B2.
Conclusion
36. In conclusion, claims 1-20 are pending, and all claims are currently rejected. No claim is allowable.
37. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JANET L COPPINS whose telephone number is (571)272-0680. The examiner can normally be reached on Monday-Friday 8:30AM-5PM EST.
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/JANET L COPPINS/Examiner, Art Unit 1628
/JARED BARSKY/Primary Examiner, Art Unit 1628