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 1-30 and 37-39 are pending in the instant application.
Claims 31-36 have been canceled.
Election/Restrictions
This action is in response to an election from a restriction requirement filed July 9th, 2025. There are 33 claims pending and 26 claims under consideration. Claims 24-30 have been withdrawn as claims to a non-elected invention. This is the first action on the merits. The present invention relates to a composition comprising a compound of formula (I) as recited at instant Claim 1 or a pharmaceutically acceptable salt thereof and a contraceptive agent.
Applicant’s election without traverse of Group I, Claims 1-23 and 37-39 and species election of medroxyprogesterone acetate as a single species of contraceptive agent in the reply filed September 9th, 2025 is acknowledged. Therefore this restriction is considered proper and thus made FINAL.
A composition comprising a compound of formula (I) and the elected species of medroxyprogesterone acetate was found to be free of the prior art. Thus, examination was extended to levonorgestrel as the single species of contraceptive agent.
Domestic Benefit
The instant application claims domestic benefit to US Provisional Application No. 63/073,140, filed on September 1st, 2020. Instant Claims 1-23 and 37 are fully supported by this application and will be evaluated with an effective filing date of September 1st, 2020.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 63/073,140, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
Regarding Claims 38-39, insufficient support is provided in the prior-filed provisional application ‘140, as no working examples of a pharmaceutical composition or a combination comprising medroxyprogesterone acetate have been provided.
To this end, Claims 38-39 will be evaluated with an effective filing date of February 14th, 2023.
Information Disclosure Statement
The Information Disclosure Statement filed on February 22nd, 2023 has been fully considered except where marked with a strikethrough.
Specification
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any of the errors of which Applicant may become aware of in the specification.
Drawings
Acknowledgement is made of the drawings received February 22nd, 2023. These drawings are acceptable.
Claim Rejections - 35 USC § 112
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 1-2, 5-21, and 37-39 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 pharmaceutical composition, combination, or kit comprising a compound of formula (I) or pharmaceutically acceptable salt thereof and levonorgestrel or levonorgestrel-butanoate, does not reasonably provide enablement for a pharmaceutical composition, combination, or kit comprising a compound of formula (I) or pharmaceutically acceptable salt thereof and any contraceptive. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use 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 a pharmaceutical composition, a combination, and/or a kit comprising a compound of formula (I) or pharmaceutically acceptable salt thereof and a contraceptive agent.
Breadth of the invention:
The scope of the claimed invention is broad, as it is drawn to compositions, combinations, and/or kits comprising any contraceptive agent. This could include an array of contraceptive agents, both known presently, and compounds discovered later that become classified as contraceptive agents.
State of the prior art and predictability in the art:
The invention is directed toward medicine and is therefore physiological in nature. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F. 2d 833, 839, 166, USPQ 18, 24 (CCPA 1970).
In terms of the law, MPEP 2107.03 states “evidence of pharmacological or other biological activity of a compound will be relevant to an asserted therapeutic use if there is reasonable correlation between the activity in question and the asserted utility. Cross v. Iizuka, 753 F. 2d 1040, 224 USPQ 739 (Fed. Cir. 1985); In re Jolles, 628 F. 2d 1322, 206 USPQ 885 (CCPA 1980); Nelson v. Bowler, 626 F. 2d 853, 206 USPQ 881 (CCPA 1980).” If correlation is lacking, it cannot be relied upon, Ex parte Powers, 220 USPQ 924; Rey-Bellet and Spiegelberg v. Engelhardt v. Schindler, 181 USPQ 453; Knapp v. Anderson, 177 USPQ 688. Indeed, the correlation must have been established “at the time the tests were performed”, Hoffman v. Klaus, 9 USPQ2d 1657.
With regard to combinations of cabotegravir (a compound of formula (I)) and contraceptive agents, Trezza et. al. (“Lack of effect of oral cabotegravir on the pharmacokinetics of a levonorgestrel/ethinyl oestradiol-containing oral contraceptive in healthy adult women”; Br J Clin Pharmacol, 83, 1499-1505, 2017; cited on Applicant’s Information Disclosure Statement filed February 22nd, 2023; hereinafter referred to as Trezza) represents the state of the prior art.
At Page 1500, First Column, Second Paragraph, Trezza teaches that in vitro and clinical studies suggest cabotegravir’s potential to be a significant perpetrator or victim of clinically significant drug interactions is low. Further, at Page 1500, Second Column, Second Paragraph, Trezza states “because of uncertainties implicit in extrapolating from in vitro and probe data, the primary objective of this present study was to confirm the lack of effect of CAB on the PK of LNG/EO in healthy women.” Ultimately, at Page 1504, Second Column, Second Paragraph, Trezza concludes that in the doses tested, CAB had no significant effect on the pharmacokinetic profile of levonorgestrel.
Taken together, Trezza demonstrates that the available data from in vitro studies are not sufficient to reliably predict whether drug-drug interactions between cabotegravir and contraceptive agents will occur. In other words, a lack of significant interaction between cabotegravir and levonorgestrel at the doses studied as presented by Trezza is not sufficient to reliably predict that cabotegravir is suitable in combination with any contraceptive agent.
Level of ordinary skill in the art:
An ordinary artisan in the area of drug development would have experience in synthesizing chemical compounds for particular activities. The synthesis of new drug candidates, while complex, is routine in the art. The process of finding new drugs that have in vitro activity against a particular biological target (i.e., receptor, enzyme, etc.) is well known. Additionally, while high throughput screening assays can be employed, developing a therapeutic method, as claimed, prior to synthesizing and testing compounds is generally not well-known or routine, given the complexity of certain biological systems.
The amount of direction provided and working examples:
Beginning at Page 11, Applicant has demonstrated pharmaceutical compositions in which cabotegravir is formulated with levonorgestrel and, separately, levonorgestrel-butanoate. Further, at Page 14, Applicant has sufficiently demonstrated the pharmacokinetic properties of compositions comprising cabotegravir and levonorgestrel or levonorgestrel-butanoate.
No data have been provided however, demonstrating that an embodiment of the instantly claimed was in possession by the Applicant in which the contraceptive agent is anything other than levonorgestrel or levonorgestrel-butanoate.
Within the specification, “specific operative embodiments or examples of the invention must be set forth. Examples and description should be of sufficient scope as to justify the scope of the claims. Markush claims must be provided with support in the disclosure for each member of the Markush group. Where the constitution and formula of a chemical compound is stated only as a probability or speculation, the disclosure is not sufficient to support claims identifying the compound by such composition or formula.” See MPEP 608.01(p).
MPEP § 2164.01(a) states “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F. 2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here that Applicant is not enabled for pharmaceutical compositions, combinations, or a kit where the contraceptive agent is anything other than levonorgestrel or levonorgestrel-butanoate.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 18, 21-22, and 37 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Trezza et. al. (“Lack of effect of oral cabotegravir on the pharmacokinetics of a levonorgestrel/ethinyl oestradiol-containing oral contraceptive in healthy adult women”; Br J Clin Pharmacol, 83, 1499-1505, 2017; cited on Applicant’s Information Disclosure Statement filed February 22nd, 2023; hereinafter referred to as Trezza).
At Page 5, Line 5 the instant specification teaches that the compound of formula (I) is cabotegravir.
At Page 1499, under Aims, Trezza teaches the study was aimed at investigating whether cabotegravir (CAB) influences the pharmacokinetics of a levonorgestrel (LNG) and ethinyl oestradiol (EO)-containing oral contraceptive.
At Page 1500, First Paragraph under Introduction, Trezza teaches that CAB is expected to be co-administered with hormonal contraceptives in both HIV-infected an uninfected woman.
At Page 1501, First Column, Second Paragraph, Trezza teaches participants in this study on days 11-21 received LNG 0.15 mg/EO 0.03 mg in combination with one CAB 30 mg tablet taken orally once daily. At Page 1504, Second Paragraph, Trezza states “These data provide confidence that CAB can be administered in combination with LNG and EO-containing OCs without clinically significant drug-drug interactions and indicate contraceptive efficacy should be maintained.” This coadministration of cabotegravir with levonorgestrel anticipates the pharmaceutical composition as recited in Claims 18 and 21-22. While the combination taught by Trezza additionally includes ethinyloestradiol, this combination is still anticipatory of Claims 18 and 21, as the combination employs the transitional phrase “comprising.” Per MPEP 2111.03, I. “The transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004)”.
Regarding Claim 37, Trezza’s teaching of coadministration of CAB with LNG/EO, as detailed above, anticipates the instantly claimed kit comprising cabotegravir and a contraceptive agent.
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.
Claims 1-3 are rejected under 35 U.S.C. 103 as being unpatentable over Trezza et. al. (“Lack of effect of oral cabotegravir on the pharmacokinetics of a levonorgestrel/ethinyl oestradiol-containing oral contraceptive in healthy adult women”; Br J Clin Pharmacol, 83, 1499-1505, 2017; cited on Applicant’s Information Disclosure Statement filed February 22nd, 2023; hereinafter referred to as Trezza).
As noted above, Trezza teaches coadministration of cabotegravir with levonorgestrel.
Trezza does not teach a pharmaceutical composition comprising cabotegravir and levonorgestrel.
Applying KSR exemplary rationale A, it would have been prima facie obvious for a person having ordinary skill in the art to formulate a composition comprising cabotegravir and levonorgestrel, as the coadministration thereof was known in the art to be tolerated. A person having ordinary skill in the art would have been motivated to do so to simplify the administration of these two compounds.
Therefore, the practice of Claims 1-3 would have been undertaken with reasonable expectation of success.
Claims 4 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Trezza in view of Wu et. al. (“Long-Acting Injectable Hormonal Dosage Forms for Contraception”; Pharm Res, 32, 2180-2191, 2015; cited on Applicant’s Information Disclosure Statement filed February 22nd, 2023; hereinafter referred to as Wu).
As noted above, Trezza obviates the limitations of Claims 1-2, from which Claim 4 depends, and anticipates Claims 18 and 21, from which Claim 23 depends.
Trezza does not teach the use of levonorgestrel-butanoate.
At Page 2183, First Column under “Drug Microcrystal Suspensions”, Wu teaches microcrystal suspension dosage forms are easy and low cost to be manufactured, and that the microcrystal suspension dosage form can achieve longer therapeutic effects than the active pharmaceutical ingredient alone. Further, Wu teaches levonorgestrel-butanoate could suppress ovulation for 5-6 months in women at a single dose in the form of microcrystal suspensions.
Applying KSR exemplary rationale B, it would have been prima facie obvious to a person having ordinary skill in the art to substitute levonorgestrel for levonorgestrel butanoate, motivated by the teaching that levonorgestrel butanoate provides the desired benefit of long-acting contraception in a form that is easy and low cost to manufacture.
Taken together, this would result in the practice of Claims 4 and 23 with a reasonable expectation of success.
Claims 5-13 are rejected under 35 U.S.C. 103 as being unpatentable over Trezza in view of Zhou (“Next Generation of Translational Long-Acting Cabotegravir”, University of Nebraska Medical Center Theses and Dissertations, 2018; section 2.4 cited on Applicant’s Information Disclosure Statement filed February 22nd, 2023; hereinafter referred to as Zhou).
As noted above, Trezza obviates the limitations of Claims 1-3.
Trezza does not teach or fairly suggest a pharmaceutical composition that further comprises polyethylene glycol, a poloxamer, polysorbate, or mannitol, and is silent with respect to the concentration of the compound of formula (I).
Regarding Claims 5-6, at Page 44, Zhou teaches PEG (polyethylene glycol) 3350 is an excipient in the CAB LAP (cabotegravir long-acting parenteral formulation). At Page 45, Table 2.3, Zhou teaches formulation stability of FA NCAB (folic acid decorated nanoformulated cabotegravir) is >3 weeks when PEG 3350 is used as an excipient. A person having ordinary skill in the art would have been motivated to include PEG 3350 as an excipient in a pharmaceutical composition to achieve comparable formulation stability. PEG 3350 would have been reasonably chosen as it was demonstrated by Zhou in Table 2.3 to provide greater stability than, for example PEG 4600, which has a reported formulation stability of 1 week.
With regard to the poloxamer, at Page 48, Second Paragraph, Zhou teaches that CAB LA (cabotegravir long-acting) formulations are nanocrystals, and that the inclusion of poloxamer 338 is essential to prevent particle agglomeration. Therefore, a person having ordinary skill in the art would have been motivated to include poloxamer 338 in the instantly claimed composition to prevent particle agglomeration.
Regarding Claims 7 and 12, at Page 50, Zhou teaches that the inclusion of mannitol maintained FA NCAB stability under long-term storage conditions. Therefore, a person having ordinary skill in the art would have been motivated to include mannitol in the instantly claimed composition to maintain the stability of the composition.
At Page 12, Zhou teaches that CAB (cabotegravir) can be formulated into 200 mg/mL or 300 mg/mL suspensions via milling process. Regarding Claims 8-9 and 13, per MPEP 2144.05, II. A., “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)”.
Regarding Claims 10-11, Zhou teaches at Page 48, Second Paragraph that the inclusion of surfactants such as polysorbate 20 is essential to prevent particle agglomeration. Therefore, a person having ordinary skill in the art would have been motivated to include polysorbate 20 in the instantly claimed composition to prevent particle agglomeration.
Conclusion
Claims 1-23 and 37-39 have been rejected.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANIEL JOHN BURKETT whose telephone number is (703)756-5390. The examiner can normally be reached Monday - Friday.
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/D.J.B./Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624