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 .
Priority
This Application is a 371 of PCT/EP2021/082583, filed Nov. 23, 2021 and claims foreign priority to EP20315465.3, filed Nov. 23, 2020 with the EPO.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08/04/2024, 04/19/2024, 01/15/2025, 04/17/2025, 05/20/2025, and 08/18/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Status
Claims 18-37 are currently pending and subject to examination.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
“(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.”
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
“Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.”
Claims 19 and 35-37 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 19 fails to further limit the subject matter of the claim upon which it depends (claim 18) because it is directed towards an inherent property, synergy, of the combination. It does not impose any further limits on the composition of claim 18, which recites a combination of two drugs.
Claims 35, 36 and 37 fail to further limit the subject matter of the claim upon which they depend because they are directed towards nonfunctional printed matter which is owed no patentable weight. “To be given patentable weight, the printed matter and associated product must be in a functional relationship.” (MPEP § 2111.05.I.A) “[W]here the printed matter and product do not depend upon each other, no functional relationship exists. For example, in a kit containing a set of chemicals and a printed set of instructions for using the chemicals, the instructions are not related to that particular set of chemicals. In re Ngai, 367 F.3d at 1339, 70 USPQ2d at 1864.”(MPEP § 2111.05.I.B).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
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 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.
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.
Claim(s) 18-37 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sanofi (EP3434272A1, Published January 30, 2019) in view of Iorfida et al. (Breast Cancer: Targets and Therapy, Vol. 12, 2020, Published March 18, 2020, pages 45-56).
Claim 18 is directed towards a combination comprising:
6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (herein “compound (1)”); and
abemaciclib.
Sanofi teaches a combination comprising:
6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (compound (1)); and
palbociclib.
Sanofi, Specification, ¶ [0001].
Sanofi teaches that “6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid, hereafter designated as "compound (1)", is a selective estrogen receptor degrader (SERD) which has complete estrogen receptor antagonist properties and accelerates the proteasomal degradation of the estrogen receptor.” (id., ¶ [0003]). Sanofi teaches that “Palbociclib… is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6. Palbociclib… is indicated for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer, in combination with an aromatase inhibitor, or in combination with fulvestrant in women who have received prior endocrine therapy.” (id., ¶ [0004]).
While Sanofi only teaches the combination of compound (1) and palbociclib, one of ordinary skill in the art would have a reasonable expectation of success to substitute abemaciclib for palbociclib because they are commonly known in the art to have similar properties: they are members of the same art recognized class – CDK 4/6 inhibitor – and are both used in combination with SERDs (e.g. compound (1) and fulvestrant) for the treatment of breast cancer.
For example, Iorfida teaches that palbociclib and abemaciclib are both CDK 4/6 inhibitors which are approved in combination with fulvestrant for the treatment of breast cancer:
The development of CDK 4/6 inhibitors has dramatically changed the therapeutic management of hormone receptor-positive (HR+) and HER2 negative metastatic breast cancer (MBC). In combination with fulvestrant, palbociclib, ribociclib and abemaciclib have each been approved for HR+/HER2- MBC following the results of randomized Phase III studies (PALOMA-3, MONALEESA-3, MONARCH-2) and shown a significant advantage in PFS. Data from clinical trials support the combination with aromatase inhibitors in the first line setting and with fulvestrant in the second line. Each agent is well tolerated, and most of the toxicities observed with this class of drugs are generally easily manageable and free from particular complications. The latest evidence from MONARCH-2 and MONALEESA-3 trials shows benefits in terms of overall survival (OS), suggesting an option of using fulvestrant in combination with CDK 4/6 inhibitors in the first line setting.
Iorfida, Abstract (emphasis added).
Iorfida teaches that the selection of palbociclib, ribociclib or abemaciclib is the choice of the treating physician as results from clinical trials show benefits for all three agents and similar efficacy while there are some differences in dosing schedule and side effect profile:
These results give the treating physician the full spectrum of CDK4/6 inhibitor choices for each individual patient, although the three CDK4/6 inhibitors have slightly different management requirements and toxicity profiles.
All three CDK4/6 inhibitors were tested in studies powered for progression-free survival and not for overall survival, but taken together the data are strong enough to support endocrine-based therapy plus a CDK4/6 inhibitor instead of endocrine therapy alone in the first/second- line setting of HR+/HER2- MBC….
Retrospective comparison of the subgroup analyses between the different studies with each CDK 4/6 inhibitor can be difficult, as each study had a different design, different patient populations, and unintentional patient biases. However, all three CDK 4/6 inhibitors have shown benefits in every single clinical subset, from liver metastases to multiple sites of metastases and to short disease-free intervals, suggesting that the three agents are likely [to] have similar efficacy.
Iorfida, col. 1, p. 53 (emphasis added).
Therefore, claim 18 was prima facie obvious at the time of filing.
Claim 19 is directed towards the combination according to claim 18, wherein the combination shows therapeutic synergy.
Sanofi teaches that “the combination of compound (1), or a pharmaceutically acceptable salt thereof, with palbociclib shows therapeutic synergy.” (Sanofi, Specification, ¶ [0008]).
One of ordinary skill in the art would also reasonably expect a combination of compound (1) and abemaciclib to show therapeutic synergy because palbociclib and abemaciclib are expected to have similar efficacy in combination with SERDs as shown by the teachings of Iorfida above in the rejection of claim 18, incorporated herein by reference.
Therefore, claim 19 was prima facie obvious at the time of filing.
Claim 20 is directed towards a method of treating cancer comprising administering to the patient in need thereof a therapeutically effective amount of compound (1) in combination with a therapeutically effective amount of abemaciclib. Claim 21 limits the cancer to breast cancer.
Sonofi teaches “a method of treating… breast cancer, comprising administering to a subject in need thereof a therapeutically effective amount of compound (1), or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of palbociclib.” (Sanofi, Specification, ¶ [0026]).
While Sanofi does not teach compound (1) in combination with abemaciclib, one of ordinary skill in the art would have a reasonable expectation of success to use either palbociclib or abemaciclib in the treatment of breast cancer because palbociclib and abemaciclib similar compounds with similar properties for the treatment of breast cancer as shown by the teachings of Iorfida as shown by the teachings of Iorfida above in the rejection of claim 18, incorporated herein by reference.
Therefore, claims 20-21 were prima facie obvious at the time of filing.
Claim 22 is directed towards the method of claim 20, wherein the compound (1) and the abemaciclib are administered simultaneously or sequentially. Claim 23 is directed towards the method of claim 22, wherein the compound (1) and abemaciclib are administered simultaneously. Claim 24 is directed towards the method of claim 22, wherein the compound (1) and abemaciclib are administered separately. Claim 25 is directed towards the method of claim 22, wherein the compound (1) and abemaciclib are administered sequentially.
Sanofi teaches that compound (1) and palbociclib can be administered simultaneously, separately or sequentially (Sanofi, Specification, ¶ [0013]).
One of ordinary skill in the art would have a reasonable expectation of success to administer compound (1) simultaneously, sequentially or separately with abemaciclib because palbociclib and abemaciclib are similar compounds with similar properties as shown by the teachings of Iorfida above in the rejection of claim 18, incorporated herein by reference.
Therefore, claims 22-25 were prima facie obvious at the time of filing.
Claims 29-33 also read on the method of treating a patient with a combination of compound (1) and abemaciclib, simultaneously or sequentially, and are rejected on the same grounds as claims 20-25. As such, claims 29-33 were prima facie obvious at the time of filing.
Claim 26 is directed towards a pharmaceutical composition comprising compound (1), abemaciclib, and at least one pharmaceutically acceptable excipient.
Sanofi teaches a pharmaceutical composition comprising compound (1), palbociclib and at least one pharmaceutically acceptable excipient (Sanofi, Specification, ¶ [0011]).
One of ordinary skill in the art would have a reasonable expectation of success to make a pharmaceutical formulation comprising compound (1) abemaciclib, and at least one pharmaceutically acceptable excipient because palbociclib and abemaciclib are similar compounds with similar properties as shown by the teachings of Iorfida above in the rejection of claim 18, incorporated herein by reference.
Therefore, claim 26 was prima facie obvious at the time of filing.
Claim 27 is directed towards a method of treating cancer comprising administering to a patient in need thereof the pharmaceutical composition according to claim 26. Claim 28 is directed towards the method according to claim 27, wherein the cancer is breast cancer.
Sanofi teaches the pharmaceutical composition above for use in the treatment of cancer (Sanofi, Specification, ¶ [0016]), particularly breast cancer (id., ¶ [0025]).
While Sanofi does not teach the composition comprising compound (1) in combination with abemaciclib for the treatment of breast, one of ordinary skill in the art would have a reasonable expectation of success to use either palbociclib or abemaciclib in a composition for the treatment of breast cancer because palbociclib and abemaciclib are similar compounds with similar properties as shown by the teachings of Iorfida above in the rejection of claim 18, incorporated herein by reference.
Therefore, claims 27-28 were prima facie obvious at the time of filing.
Claim 34 is directed towards a kit comprising:
a first pharmaceutical composition comprising compound (1), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient
a second pharmaceutical composition comprising abemaciclib and at least one pharmaceutically acceptable excipient;
wherein the first pharmaceutical composition and the second pharmaceutical composition are in separate compartments.
Sanofi teaches a kit which comprises:
a first pharmaceutical composition comprising compound (1), or a pharmaceutically acceptable salt thereof, as well as at least one pharmaceutically acceptable excipient;
a second pharmaceutical composition comprising palbociclib, as well as at least one pharmaceutically acceptable excipient;
both pharmaceutical compositions (i) and (ii) being in separate compartments and being intended to be independently administered, each administration with regards to the other one being simultaneous, separated or spread out over time.
Sanofi, Specification, ¶ [0014].
While Sanofi only teaches a kit comprising compound (1) and palbociclib, one of ordinary skill in the art would have a reasonable expectation of success to use either palbociclib or abemaciclib in a kit because palbociclib and abemaciclib are similar compounds with similar properties as shown by the teachings of Iorfida above in the rejection of claim 18, incorporated herein by reference.
Therefore, claim 34 was prima facie obvious at the time of filing.
Claim 35 is directed towards the kit of claim 34, further comprising a package insert indicating that the first and second pharmaceutical compositions are administered for the treatment of cancer. Claim 36 is directed towards the kit of claim 35, wherein the cancer is breast cancer.
Sanofi teaches that the kit can further comprise a packing material and a “package insert contained within said packaging material, indicating that said combination, pharmaceutical composition or pharmaceutical kit is administered to a patient for the treatment of cancer.” (Sanofi, Specification, ¶ [0028]). Sanofi teaches that the particular indication for a combination of compound (1) and the CDK 4/6 inhibitor is breast cancer (id., ¶ [0025]).
While Sanofi only teaches a kit comprising compound (1) and palbociclib, one of ordinary skill in the art would have a reasonable expectation of success to use either palbociclib or abemaciclib in a kit for the treatment of breast cancer because palbociclib and abemaciclib are similar compounds with similar properties in the treatment of cancer as shown by the teachings of Iorfida above in the rejection of claim 18, incorporated herein by reference.
Therefore, claims 35-36 were prima facie obvious at the time of filing.
Claim 37 is directed towards the kit of claim 34, further comprising a package insert indicating that the first and second pharmaceutical compositions are administered simultaneously or sequentially with respect to each other.
As shown in the rejection of claim 34, Sanofi teaches that the compound (1) and palbociclib are intended for sequential or simultaneous administration.
While Sanofi only teaches a kit comprising compound (1) and palbociclib, one of ordinary skill in the art would have a reasonable expectation of success to use either palbociclib or abemaciclib in a kit with instructions for sequential or simultaneous administration because palbociclib and abemaciclib are similar compounds with similar properties as shown by the teachings of Iorfida above in the rejection of claim 18, incorporated herein by reference.
Therefore, claim 37 was prima facie obvious at the time of filing.
Given the above teachings, the invention as a whole was prima facie obvious at the time of filing. The present invention is clearly nothing more than a simple substitution of one known element for another to obtain predictable results. Sanofi teaches an almost complete resolution of tumors from a combination of compound (1) and palbociclib and Iorfida teaches that palbociclib and abemaciclib have similar efficacies when combined with SERDs like compound (1).
Compare the instant Figs. 1-2 with Figs. 2-3 of Sanofi:
PNG
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481
638
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(Instant Fig. 1).
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493
621
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(Sanofi Fig. 2).
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467
618
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438
634
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(Instant Fig. 1) (Sanofi, Fig. 3).
Given the above teachings there is nothing unexpected about the reduction in tumor volume with a combination of compound (1) and abemaciclib.
Nonstatutory 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.
Claims 18-37 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11,260,057 B2 (herein the ‘057 patent) in view of Iorfida et al. (Breast Cancer: Targets and Therapy, Vol. 12, 2020, Published March 18, 2020, pages 45-56).
Although the claims at issue are not identical, they are not patentably distinct because the instant claims are directed towards a combination of compound (1) and abemaciclib, kits and pharmaceutical compositions thereof, and methods of treating cancer with this combination, while the claims of the ‘057 patent are directed towards a combination of compound (1) and palbociclib, kits and pharmaceutical compositions thereof, and methods of treating cancer with this combination. The ‘057 patent is the U.S. version of the Sanofi patent referenced in the 35 U.S.C. 103 rejection above, incorporated herein by reference. Given the teachings of Iorfida, which show that abemaciclib and palbociclib have similar efficacies in combination with SERDs such as compound (1) for the treatment of breast cancer, one of ordinary skill in the art would have a reasonable expectation of success to substitute abemaciclib for palbociclib in the combination/ method/ pharmaceutical composition/ kit.
Claims 18-37 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 18-37 of copending Application No. 12/286,510 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are directed towards a combination of compound (1) and abemaciclib, kits and pharmaceutical compositions thereof, and methods of treating cancer with this combination, while the claims of the ‘057 patent are directed towards a combination of compound (1) and ribociclib, kits and pharmaceutical compositions thereof, and methods of treating cancer with this combination.
Given the teachings of Iorfida, which show that abemaciclib and ribociclib have similar efficacies in combination with SERDs such as compound (1) for the treatment of breast cancer, one of ordinary skill in the art would have a reasonable expectation of success to substitute abemaciclib and ribociclib in the combination/ method/ pharmaceutical composition/ kit. The 35 U.S.C. 103 rejection above is incorporated herein by reference, which shows the equivalency of palbociclib, ribociclib and abemaciclib.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is found to be allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HEATHER DAHLIN whose telephone number is (571)270-0436. The examiner can normally be reached 9-5.
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/HEATHER DAHLIN/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629