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 Claims
Claims 2-32 are pending.
Priority
Instant application 18/767,400, filed 07/09/2024 claims priority as follows:
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Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. 15/763,698, filed on 03/27/2018.
Information Disclosure Statement
All references from IDS(s) received 11/26/2024 have been considered unless marked with a strikethrough.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 2-31 in the reply filed on 04/15/2026 is acknowledged. Claim 32 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 04/15/2026.
Applicant’s election without traverse of the species compound (2S,3S)-3-(4-chlorophenyl)-3- [(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1 S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3- oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoic acid in the reply filed on 11/26/2024 and the species cancer colorectal cancer is acknowledged. However, in the course of the search, the election of species requirement was withdrawn. Claims 2-31 are examined on the merits herein.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 2-31 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method for treating cancer, wherein the cancer is characterized by wild-type p53 and MDM2 overexpression; or wherein the cancer is mediated by MDM2/p53 interaction, does not reasonably provide enablement for a method for treating cancer wherein the is p53 wild-type alone, or mediated by MDM2 alone, or has p14ARF loss alone, or has MDM2 amplification or overexpression alone. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (1) The breadth of the claims, (2) The nature of the invention, (3) The state of the prior art, (4) The level of one of ordinary skill, (5) The level of predictability in the art, (6) The amount of direction provided by the inventor, (7) The existence of working examples and (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Nature of the invention:
The invention is drawn to small-molecule compounds built around an isoindolinone scaffold, Formula (Ir). The compounds are designed to block the interaction between MDM2 and p53, a protein-protein binding event that normally suppresses p53 activity. By preventing MDM2 from shutting down p53, the compounds are intended to restore p53’s tumor-suppressing function.
Breadth of the claims:
The claims are drawn to the use of compounds of Formula (Ir) for treating cancer. Claim 2 contains the repeated use of “and/or” across six separate characteristics of the cancer (p53 wild-type, and/or mediated by MDM2, and/or has MDM2 overexpression, etc.). The repeated use of “and/or” creates 26 = 64 possible combinations of characteristics for the patient’s cancer. The effect is that the scope of the cancers encompassed by claim 2 is essentially any cancer having at least one of the recited characteristics.
Level of ordinary skill in the art:
The artisans using applicant’s method would be a collaborative team of synthetic chemists and/or health practitioners, possessing commensurate degree level and/or skill in the art, as well as several years of professional experience.
The level of skill in the art is high; however, due to the unpredictability in the pharmaceutical art, it is noted that each embodiment of the invention is required to be individually assessed for physiological activity by in vitro or in vivo screening to determine which compounds exhibit the desired pharmacological activity and which diseases would benefit from this activity.
State of the prior art and predictability in the art:
At the priority date (September 29, 2015), several MDM2-p53 inhibitors were in clinical development. See, for example, ZHAO (Journal of Medicinal Chemistry, vol. 58, no. 3, Feb. 2015, pp. 1038–52). Zhao is a review drawn to MDM2 inhibitors in clinical trials for the treatment of human cancer (see entire document). Zhao discloses that at the time of publication, seven small molecule MDM2 inhibitors had advanced into clinical trials (Zhao, Table 1). The prior art thus established that MDM2 inhibitors as a class could exhibit anti-tumor activity in vitro and in animal models, and some had entered clinical trials.
However, Zhao also notes that only ~7% of all human cancers have an amplified MDM2 gene, and a higher frequency of MDM2 gene amplification occurs in certain tumor types including well-differentiated liposarcomas (>80%), soft tissue tumors (20%), osteosarcomas (16%), and esophageal carcinomas (13%) (page 1048, right side, 2nd para.). Zhao further discloses that MDM2 inhibitors are only effective in targeting tumor cells with wild-type p53 (page 1049, left side).
Moreover, Zhao demonstrates that the path from MDM2 binding potency to clinical efficacy was uncertain. Zhao discloses that since MDM2 inhibitors also activate p53 in normal cells and normal tissues, there is concern that activation of p53 can cause toxicity in those normal tissues sensitive to p53 activation, such as bone marrow, spleen, and small intestines (page 1049, left side). Indeed, data from phase I clinical trials of certain compounds (3 and 6 in Zhao) showed that MDM2 inhibitors can cause thrombocytopenia, which is a major dose-limiting toxicity. Therefore, determination of appropriate dose schedules that can achieve robust p53 activation and strong anti-tumor activity but have manageable on-target toxicity was a known challenge in the development of MDM2 inhibitors, and one that applicant does not appear to have demonstrated a meaningful solution to for the claimed compounds.
Pharmacological activity in general is a very unpredictable area. A skilled artisan, taking Zhao as close prior art, would not readily predict which cancers would be successfully treated using the compounds claimed by applicant. Note that in cases involving physiological activity such as the instant case, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved.” See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
The amount of direction provided and working examples:
The specification provides excellent direction for making the claimed compounds. 137 synthesis examples are provided. A person of ordinary skill could readily make the claimed compounds. However, direction for using the claimed compounds to treat cancer in patients is far more limited. The specification reports (Table 1) MDM2 IC50 values for all 137 example compounds. Many compounds demonstrate potent MDM2 binding. Additionally, in vitro data is provided in the form of a cell proliferation assay in two osteosarcoma cell lines (SJSA-1 and SN40R2). No data is presented for any other cancer type.
Moreover, no in vivo data is provided. No pharmacokinetic data, dose-response data, or toxicology data are provided. The cancer-type guidance is generic. The specification provides an exhaustive list of cancer types, but no data demonstrating activity in any cancer type other than osteosarcoma. The specification states that the claimed compounds “may have increased in vivo efficacy in cancer cell lines and in vivo models” (page 113, 2nd para.), but this is aspirational language, not a report of actual results.
See MPEP 2164.02 (“Compliance with the enablement requirement of 35 USC 112, first paragraph, does not turn on whether an example is disclosed ... Lack of a working example, however, is a factor to be considered, especially in a case involving an unpredictable and undeveloped art.”).
Quantity of experimentation needed to use the invention based on the content of the disclosure:
The quantity of experimentation needed is undue experimentation. One of skill in the art would need to determine what cancers other than those characterized by wild-type p53 and MDM2 overexpression could be treated by the claimed compounds. Further, they would need to determine appropriate dose schedules that can achieve robust p53 activation and strong anti-tumor activity but have manageable on-target toxicity, i.e. they would need to solve a known challenge in the development of MDM2 inhibitors. This would involve conducting in vivo pharmacokinetic studies to determine whether compounds are orally bioavailable, metabolically stable, and able to reach tumors at therapeutic concentrations; conducting animal efficacy studies (e.g. xenograft models) for each cancer type claimed; and conducting dose-escalation studies in animal models/humans for each cancer type claimed. This experimentation would be extensive, costly, time-consuming, and unpredictable in outcome.
Therefore, claims 2-31 are rejected.
Double Patenting
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 § 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).
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.
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.
10,544,132
Claims 2-31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 and 17-18 of U.S. Patent No. 10,544,132 (“the ‘132 patent”) in view of Golding (WO 2009/156735 A2; published December 30, 2009; cited in IDS); Mohammad (Molecular Cancer, vol. 8, no. 1, Dec. 2009, p. 115); Andreeff (Blood, vol. 116, no. 21, Nov. 2010, p. 657); Lu (Oncotarget, vol. 3, no. 10, Oct. 2012, pp. 1052–53); and/or Lakoma (Cell Death Discovery, vol. 1, no. 1, Aug. 2015, pp. 1–9).
With respect to instant claims 2-26, The claims of the ‘132 patent recite compounds of formula (Ir):
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which are identical to or substantially overlap with the compounds of formula (Ir) of the instant claims. Additionally, the ‘132 patent recites methods of treating cancer and inhibiting the interaction of p53 with MDM2 comprising administering the compounds of formula (Ir):
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With respect to instant claim 27, the ‘132 patent recites treating lung cancer.
The ‘132 patent fails to recite the specific lung cancer as non-small cell lung cancer (“NSCLC”).
However, the use of isoindolinone MDM2 antagonists to treat various cancers including NSCLC was known in the prior art before the effective filing date of the instant application. For example, Golding discloses isoindolinone compounds of Formula I (see also the compounds of Tables 1-5 at pages 16-37) as MDM2 inhibitors:
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Note that the compounds of Golding have the same isoindolinone core of the instantly claimed compounds. Golding further discloses methods of treating the following cancers, including NSCLC, comprising administering compounds of formula I (see pg. 38, line 9):
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Applying KSR prong (A), it would have been prima facie obvious to administer the compounds recited in the ‘132 patent in a method of treating NSCLC. A skilled artisan would have reasonably predicted that treating NSCLC with the compounds recited in the ‘132 patent would succeed because said compounds are isoindolinone MDM2 inhibitors, and Golding teaches administering isoindolinone MDM2 inhibitors to treat NSCLC.
With respect to instant claim 28, the ‘132 patent recites treating lymphoma.
The ‘132 patent fails to recite the specific lymphoma as diffuse large B-cell lymphoma, follicular lymphoma, or T-cell lymphoma.
However, the use of MDM2 antagonists to treat lymphomas such as B-cell lymphoma and follicular lymphoma was known in the prior art before the effective filing date of the instant application. For example, Mohammad discloses treating follicular lymphoma by administering the MDM2 antagonist MI-319 (see Abstract and Fig. 1):
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Applying KSR prong (A), it would have been prima facie obvious to administer the compounds recited in the ‘132 patent in a method of treating a B-cell lymphoma or follicular lymphoma. A skilled artisan would have reasonably predicted that treating follicular lymphoma with the compounds recited in the ‘132 patent would succeed because said compounds are MDM2 antagonists, and Mohammad teaches administering MDM2 antagonists to treat follicular lymphoma.
With respect to instant claim 29, the ‘132 patent recites treating leukemia.
The ‘132 patent fails to recite the specific leukemia as acute myeloid leukemia (“AML”), acute lymphocytic leukemia (“ALL”), chronic lymphocytic leukemia (“CLL”), or chronic myeloid leukemia (“CML”).
However, the use of MDM2 antagonists to treat leukemia such as ALL, AML and CLL was known in the prior art before the effective filing date of the instant application. For example, Andreeff discloses treating AML, ALL and CLL by administering the MDM2 antagonist RG7112 (see Results, Conclusions).
Applying KSR prong (A), it would have been prima facie obvious to administer the compounds recited in the ‘132 patent in a method of treating leukemia such as AML, ALL, and CLL. A skilled artisan would have reasonably predicted that treating leukemia with the compounds recited in the ‘132 patent would succeed because said compounds are MDM2 antagonists, and Andreeff teaches administering MDM2 antagonists to treat leukemia.
With respect to instant claim 30, the ‘132 patent fails to recite a myeloproliferative disorder or the specific myeloproliferative disorders polycythemia vera (“PV”), essential thrombocythemia (“ET”), or primary myelofibrosis (“PMF”).
However, the use of MDM2 antagonists to treat myeloproliferative disorders such as PV, ET, or PMF was known in the prior art before the effective filing date of the instant application.
For example, Lu discloses treating myeloproliferative neoplasms such as PV by administering the MDM2 antagonist nutlin-3 and RG7112 (see pg. 1052, col. 2, para. 2-3).
Applying KSR prong (A), it would have been prima facie obvious to administer the compounds recited in the ‘132 patent in a method of treating a myeloproliferative disorder such as PV, ET, or PMF. A skilled artisan would have reasonably predicted that treating a myeloproliferative disorder with the compounds recited in the ‘132 patent would succeed because said compounds are MDM2 antagonists, and Lu teaches administering MDM2 antagonists to treat myeloproliferative disorders.
With respect to instant claim 31, the ‘132 patent fails to recite a neuroblastoma, glioblastoma, a myeloproliferative disorder, a hematological malignancy, salivary gland cancer, or myelodysplastic syndrome.
However, the use of MDM2 antagonists to treat neuroblastoma was known in the prior art before the effective filing date of the instant application.
For example, Lakoma discloses treating neuroblastoma by administering the MDM2 antagonist RG7388 (see Abstract).
Applying KSR prong (A), it would have been prima facie obvious to administer the compounds recited in the ‘132 patent in a method of treating neuroblastoma. A skilled artisan would have reasonably predicted that treating neuroblastoma with the compounds recited in the ‘132 patent would succeed because said compounds are MDM2 antagonists, and Lakoma teaches administering MDM2 antagonists to treat neuroblastoma.
10,981,898
Claims 2-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 and 25-26 of U.S. Patent No. 10,981,898 (“the ‘898 patent”) in view of Golding (WO 2009/156735 A2; published December 30, 2009); Mohammad (Molecular Cancer, vol. 8, no. 1, Dec. 2009, p. 115); Andreeff (Blood, vol. 116, no. 21, Nov. 2010, p. 657); Lu (Oncotarget, vol. 3, no. 10, Oct. 2012, pp. 1052–53); and/or Lakoma (Cell Death Discovery, vol. 1, no. 1, Aug. 2015, pp. 1–9).
With respect to instant claims 2-26, The claims of the ‘898 patent recite compounds of formula (Ir):
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which are identical to or substantially overlap with the compounds of formula (Ir) of the instant claims. Additionally, the ‘898 patent recites methods of treating cancer and inhibiting the interaction of p53 with MDM2 comprising administering the compounds of formula (Ir):
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With respect to instant claim 27, the ‘898 patent recites treating lung cancer.
The ‘898 patent fails to recite the specific lung cancer as non-small cell lung cancer (“NSCLC”).
However, the use of isoindolinone MDM2 antagonists to treat various cancers including NSCLC was known in the prior art before the effective filing date of the instant application. For example, Golding discloses isoindolinone compounds of Formula I (see also the compounds of Tables 1-5 at pages 16-37) as MDM2 inhibitors:
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Note that the compounds of Golding have the same isoindolinone core of the instantly claimed compounds. Golding further discloses methods of treating the following cancers, including NSCLC, comprising administering compounds of formula I (see pg. 38, line 9):
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Applying KSR prong (A), it would have been prima facie obvious to administer the compounds recited in the ‘898 patent in a method of treating NSCLC. A skilled artisan would have reasonably predicted that treating NSCLC with the compounds recited in the ‘898 patent would succeed because said compounds are isoindolinone MDM2 inhibitors, and Golding teaches administering isoindolinone MDM2 inhibitors to treat NSCLC.
With respect to instant claim 28, the ‘898 patent recites treating lymphoma.
The ‘898 patent fails to recite the specific lymphoma as diffuse large B-cell lymphoma, follicular lymphoma, or T-cell lymphoma.
However, the use of MDM2 antagonists to treat lymphomas such as B-cell lymphoma and follicular lymphoma was known in the prior art before the effective filing date of the instant application. For example, Mohammad discloses treating follicular lymphoma by administering the MDM2 antagonist MI-319 (see Abstract and Fig. 1):
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Applying KSR prong (A), it would have been prima facie obvious to administer the compounds recited in the ‘898 patent in a method of treating a B-cell lymphoma or follicular lymphoma. A skilled artisan would have reasonably predicted that treating follicular lymphoma with the compounds recited in the ‘898 patent would succeed because said compounds are MDM2 antagonists, and Mohammad teaches administering MDM2 antagonists to treat follicular lymphoma.
With respect to instant claim 29, the ‘898 patent recites treating leukemia.
The ‘898 patent fails to recite the specific leukemia as acute myeloid leukemia (“AML”), acute lymphocytic leukemia (“ALL”), chronic lymphocytic leukemia (“CLL”), or chronic myeloid leukemia (“CML”).
However, the use of MDM2 antagonists to treat leukemia such as ALL, AML and CLL was known in the prior art before the effective filing date of the instant application. For example, Andreeff discloses treating AML, ALL and CLL by administering the MDM2 antagonist RG7112 (see Results, Conclusions).
Applying KSR prong (A), it would have been prima facie obvious to administer the compounds recited in the ‘898 patent in a method of treating leukemia such as AML, ALL, and CLL. A skilled artisan would have reasonably predicted that treating leukemia with the compounds recited in the ‘898 patent would succeed because said compounds are MDM2 antagonists, and Andreeff teaches administering MDM2 antagonists to treat leukemia.
With respect to instant claims 30, the ‘898 patent fails to recite a myeloproliferative disorder or the specific myeloproliferative disorders polycythemia vera (“PV”), essential thrombocythemia (“ET”), or primary myelofibrosis (“PMF”).
However, the use of MDM2 antagonists to treat myeloproliferative disorders such as PV, ET, or PMF was known in the prior art before the effective filing date of the instant application.
For example, Lu discloses treating myeloproliferative neoplasms such as PV by administering the MDM2 antagonist nutlin-3 and RG7112 (see pg. 1052, col. 2, para. 2-3).
Applying KSR prong (A), it would have been prima facie obvious to administer the compounds recited in the ‘898 patent in a method of treating a myeloproliferative disorder such as PV, ET, or PMF. A skilled artisan would have reasonably predicted that treating a myeloproliferative disorder with the compounds recited in the ‘898 patent would succeed because said compounds are MDM2 antagonists, and Lu teaches administering MDM2 antagonists to treat myeloproliferative disorders.
With respect to instant claim 31, the ‘898 patent fails to recite a neuroblastoma, glioblastoma, a myeloproliferative disorder, a hematological malignancy, salivary gland cancer, or myelodysplastic syndrome.
However, the use of MDM2 antagonists to treat neuroblastoma was known in the prior art before the effective filing date of the instant application.
For example, Lakoma discloses treating neuroblastoma by administering the MDM2 antagonist RG7388 (see Abstract).
Applying KSR prong (A), it would have been prima facie obvious to administer the compounds recited in the ‘898 patent in a method of treating neuroblastoma. A skilled artisan would have reasonably predicted that treating neuroblastoma with the compounds recited in the ‘898 patent would succeed because said compounds are MDM2 antagonists, and Lakoma teaches administering MDM2 antagonists to treat neuroblastoma.
11,261,171
Claims 2-31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 11,261,171 (“the ‘171 patent”) in view of Golding (WO 2009/156735 A2; published December 30, 2009).
With respect to instant claims 2-31, the claims of the ‘171 patent recite administering compounds of formula I to treat various cancers (see claims 1, 23 and 24):
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Notably, the ‘171 patent recites compounds that comprise a heteroaryl ring substituted with R1, specifically pyridine, pyrimidine, pyrazine, pyridazine, or an N-oxide thereof.
The ‘171 patent fails to recite compounds having a phenyl ring substituted with R1, as is the case for the instantly claimed compounds.
However, a prima facie case of obviousness may be made when chemical compounds
have very close structural similarities and similar utilities. See MPEP 2144.09. In the instant
case, the compounds taught by the ‘171 patent are taught as inhibitors of the MDM2-p53 interaction, which is the same utility disclosed for the genus of compounds recited in the instant claims. Additionally, the isoindolinone compounds of the ‘171 patent differ only by substitution of a phenyl ring with a pyridyl or other azine, and thus have very close structural similarities.
A review of the prior art identifies Golding, which teaches isoindolinone inhibitors of the MDM2-p53 interaction having both aryl and heteroaryl rings at the position substituted by R1 (see Tables 1-5 at pages 16-37). For example, a comparison is provided below for NU8429 and NU8416:
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Notably, substituting the pyridyl group with a 4-bromophenyl group not only retains, but also apparently improves the potency of the compound for MDM2.
Applying KSR prong (B), it would have been prima facie obvious to substitute the heteroaryl ring substituted by R1 in the compounds recited by the ‘171 patent with a phenyl ring substituted by R1 to arrive at the method of treating cancer of the instant claims. A skilled artisan would have readily predicted that substituting the heteroaryl with a phenyl would result in compounds having the same utility for treating cancer because Golding teaches that such a substitution retains and improves the potency of similar isoindolinone compounds.
10,526,311
Claims 2-31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13, 15, and 17-25 of U.S. Patent No. 10,526,311 (“the ‘311 patent”) in view of Golding (WO 2009/156735 A2; published December 30, 2009); Mohammad (Molecular Cancer, vol. 8, no. 1, Dec. 2009, p. 115); Andreeff (Blood, vol. 116, no. 21, Nov. 2010, p. 657); Lu (Oncotarget, vol. 3, no. 10, Oct. 2012, pp. 1052–53); and/or Lakoma (Cell Death Discovery, vol. 1, no. 1, Aug. 2015, pp. 1–9).
With respect to instant claims 2-27, the claims of the ‘311 patent recite compounds of formula (I):
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which differ from the instantly claimed compounds by substitution of a phenyl with a heteroaryl ring substituted with R1, specifically pyridine, pyrimidine, pyrazine, pyridazine, or an N-oxide thereof. Additionally, the ‘311 patent recites a method of inhibiting the interaction of p53 with MDM2 comprising administering the compounds of formula (Ir):
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The ‘311 patent fails to recite compounds having a phenyl ring substituted with R1, and methods for treating cancer or the specific cancers of the instant claims.
However, a prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. See MPEP 2144.09. In the instant case, the compounds taught by the ‘311 patent are taught as inhibitors of the MDM2-p53 interaction, which is the same utility disclosed for the genus of compounds recited in the instant claims. Additionally, the isoindolinone compounds of the ‘311 patent differ only by substitution of a phenyl ring with a pyridyl or other azine, and thus have very close structural similarities.
A review of the prior art identifies Golding, which teaches isoindolinone inhibitors of the MDM2-p53 interaction having both aryl and heteroaryl rings at the position substituted by R1 (see formula I and Tables 1-5 at pages 16-37). For example, a comparison is provided below for NU8429 and NU8416:
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Notably, substituting the pyridyl group with a 4-bromophenyl group not only retains, but also apparently improves the potency of the compound for MDM2.
Golding further discloses methods of treating the following cancers comprising administering compounds of formula I (see pg. 38, line 9):
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Applying KSR prong (B), it would have been prima facie obvious to substitute the heteroaryl ring substituted by R1 in the compounds recited by the ‘311 patent with a phenyl ring substituted by R1 to arrive at the method of treating cancer of the instant claims. A skilled artisan would have readily predicted that substituting the heteroaryl with a phenyl would result in compounds having the same utility for treating cancer because Golding teaches that such a substitution retains and improves the potency of similar isoindolinone compounds. Additionally, Golding teaches that inhibitors of the interaction of p53 with MDM2 have utility for treating cancers listed in instant claims 1 and 23.
With respect to instant claim 28, the recitations of the ‘311 patent in view of Golding teach treating lymphoma.
The recitations of the ‘311 patent in view of Golding fail to teach the specific lymphoma as diffuse large B-cell lymphoma, follicular lymphoma, or T-cell lymphoma.
However, the use of MDM2 antagonists to treat lymphomas such as B-cell lymphoma and follicular lymphoma was known in the prior art before the effective filing date of the instant application. For example, Mohammad discloses treating follicular lymphoma by administering the MDM2 antagonist MI-319 (see Abstract and Fig. 1):
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Applying KSR prong (A), it would have been prima facie obvious to administer the compounds taught by the ‘311 patent in view of Golding in a method of treating a B-cell lymphoma or follicular lymphoma. A skilled artisan would have reasonably predicted that treating follicular lymphoma with said compounds would succeed because said compounds are MDM2 antagonists, and Mohammad teaches administering MDM2 antagonists to treat follicular lymphoma.
With respect to instant claim 29, the recitations of the ‘311 patent in view of Golding teach treating leukemia.
The recitations of the ‘311 patent in view of Golding fail to teach the specific leukemia as acute myeloid leukemia (“AML”), acute lymphocytic leukemia (“ALL”), chronic lymphocytic leukemia (“CLL”), or chronic myeloid leukemia (“CML”).
However, the use of MDM2 antagonists to treat leukemia such as ALL, AML and CLL was known in the prior art before the effective filing date of the instant application. For example, Andreeff discloses treating AML, ALL and CLL by administering the MDM2 antagonist RG7112 (see Results, Conclusions).
Applying KSR prong (A), it would have been prima facie obvious to administer the compounds taught by the ‘311 patent in view of Golding in a method of treating leukemia such as AML, ALL, and CLL. A skilled artisan would have reasonably predicted that treating leukemia with said compounds would succeed because said compounds are MDM2 antagonists, and Andreeff teaches administering MDM2 antagonists to treat leukemia.
With respect to instant claims 30, the recitations of the ‘311 patent in view of Golding fail to teach a myeloproliferative disorder or the specific myeloproliferative disorders polycythemia vera (“PV”), essential thrombocythemia (“ET”), or primary myelofibrosis (“PMF”).
However, the use of MDM2 antagonists to treat myeloproliferative disorders such as PV, ET, or PMF was known in the prior art before the effective filing date of the instant application.
For example, Lu discloses treating myeloproliferative neoplasms such as PV by administering the MDM2 antagonist nutlin-3 and RG7112 (see pg. 1052, col. 2, para. 2-3).
Applying KSR prong (A), it would have been prima facie obvious to administer the compounds taught by the ‘311 patent in view of Golding in a method of treating a myeloproliferative disorder such as PV, ET, or PMF. A skilled artisan would have reasonably predicted that treating a myeloproliferative disorder with said compounds would succeed because said compounds are MDM2 antagonists, and Lu teaches administering MDM2 antagonists to treat myeloproliferative disorders.
With respect to instant claim 31, the recitations of the ‘311 patent in view of Golding fail to teach a neuroblastoma, glioblastoma, a myeloproliferative disorder, a hematological malignancy, salivary gland cancer, or myelodysplastic syndrome.
However, the use of MDM2 antagonists to treat neuroblastoma was known in the prior art before the effective filing date of the instant application.
For example, Lakoma discloses treating neuroblastoma by administering the MDM2 antagonist RG7388 (see Abstract).
Applying KSR prong (A), it would have been prima facie obvious to administer the compounds taught by the ‘311 patent in view of Golding in a method of treating neuroblastoma. A skilled artisan would have reasonably predicted that treating neuroblastoma with said compounds would succeed because said compounds are MDM2 antagonists, and Lakoma teaches administering MDM2 antagonists to treat neuroblastoma.
12,071,429
Claims 2-31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of U.S. Patent No. 12,071,429. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims recite a method for treating cancer, wherein the cancer is selected from colon cancer, colorectal cancer, lung cancer, mesothelioma, breast cancer, osteosarcoma, fibrosarcoma, melanoma, liver cancer, leukemia, lymphoma, prostate cancer, liposarcoma, pancreatic cancer, ovarian cancer, gastric cancer, bladder cancer, epithelial cancer, multiple myeloma, soft tissue sarcoma, neuroblastoma, glioblastoma, a myeloproliferative disorder, a hematological malignancy, salivary gland cancer, and myelodysplastic syndrome, comprising administering the same compounds of Formula (Ir) instantly claimed. The claims are therefore directed to overlapping subject matter.
Moreover, the compounds claimed in the ‘429 patent are disclosed for their utility as inhibitors of the MDM2-p53 interaction (see, e.g., title, abstract, background of the invention). It would have therefore been prima facie obvious to administer the compounds recited in the ‘429 patent to a patient having a cancer mediated by the MDM2-p53 interaction.
Conclusion
Claims 2-31 are rejected. Claim 32 is withdrawn.
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/K.N./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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