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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 66-77 and 85, in the reply filed on August 12, 2026 is acknowledged. Claims 78-84 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on August 12, 2026.
Claim Objections
Claim 70 is objected to because of the following informalities: in limitation (i) it is unclear how an embryo transfer is part of the “natural conception Also in the last line “IU” should be “the (or said) IUI”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 67, 68, and 72 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 67 and 68 recite “about… µg to about … µg”, and claim 72 recites “no more than about 5 days”. The “about” in these phrases indefinite. The specification does not define the extent of “about”. Also it does not contain any disclosure that would indicate the extent of “about”. Paragraph [0044] for example lists a series of numerical values following “about, e.g., “most preferably about 0.05 μg to about 2.5 μg”. The range of the minimum to the maximum comprises a fifty-fold difference, meaning it does not aid in interpreting “about”. Paragraph [0047] states “5 days prior to the embryo transfer, or 4 days prior to the embryo transfer, or 3 days…”. Thus it appears “about” would not mean one whole day; however it is unclear whether 5.6 days is “about 5 days”. Therefore the skilled person would not be apprised of the metes and bounds of the claims.
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 66-77 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 of enhancing embryo implantation in a subject in need thereof, wherein the method comprises administering to the uterine cavity of the subject a formulation comprising copper, wherein the copper is provided in solution, foam or gel form, wherein the formulation is administered to the uterine cavity of the subject in an amount effective to stimulate endometrial production of leukaemia inhibitory factor (LIF) and/or vascular endothelial growth factor (VEGF), wherein the formulation provides copper ions to the uterine fluid in an amount in the range of about 0.025 μg to about 12.5 μg per dose or wherein the formulation comprises 20-200 μM copper ions, it, does not reasonably provide enablement for practicing the method at a dose outside the ranges or for any subject who is capable of pregnancy without the method of enhanced embryo implantation.
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. Claim 66 encompasses a method of enhancing embryo implantation in any subject, regardless of the subject’s pregnancy history or menstrual cycle, by administering to the uterine cavity of the subject a formulation comprising copper, wherein the copper is provided in solution, foam or gel form, “in an amount effective to stimulate endometrial production of leukaemia inhibitory factor (LIF) and/or vascular endothelial growth factor (VEGF)”. While Applicant’s disclosure may be enabling for such method wherein the dose is controlled as disclosed, for subjects who are at specific stages of her menstrual cycle and at risk of implantation failure, it does not enable a method wherein any dose could be administered for “enhancing embryo implantation”. While claims 67-69 recite the dose ranges of copper ions, they are relevant to the subject and the protocol of administration (for example in claim 70) disclosed.
In re Wands, 858 F.2d 731, 736-40, 8 USPQ2d 1400, 1403-07 (Fed. Cir. 1988), set forth eight factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." (MPEP § 2164.01)
a. The breadth of the claim: The rejected claims are drawn to a method of enhancing embryo implantation in any subject, regardless of the subject’s pregnancy history or the stage in a menstrual cycle, comprising administering to the uterine cavity of the subject a formulation comprising copper, wherein the copper is provided in solution, foam or gel form, in any amount effective to stimulate endometrial production of leukaemia inhibitory factor (LIF) and/or vascular endothelial growth factor (VEGF). The rejected claims encompass administering any amount of a formulation comprising any form and any concentration of copper, as long as it is found effective for stimulating endometrial production of LIF and/or VEGF to any degree in any subject.
b. Nature of the invention: The nature of the invention is methods of improving the rate of embryo implantation in any subject’s uterus, whether having had prior natural pregnancies or not, by administering copper in an amount that increases the endometrial production of leukaemia inhibitory factor (LIF) and/or vascular endothelial growth factor (VEGF).
c. The state of the prior art: Chou (Chou, C.-H., et al., Divergent endometrial inflammatory cytokine expression at peri-implantation period and after the stimulation by copper intrauterine device, Scientific Reports, 5:15157 (2015)) reports “prominent TNF-α staining on the [mice] endometrium after Cu-IUD stimulation, and in vitro culture of human endometrial glandular cells with Cu induced TNF-α secretion” which led to “in vitro THP-1 cells chemotaxis, and reduced embryo implantation rates” (abstract (emphasis added)). On the other hand Mao (Mao, X., et al., Short-term copper intrauterine device placement improves the implantation and pregnancy rates in women with repeated implantation failure, Fertility and Sterility, 108, 55-61 (2017); see IDS) reports that in women with repeated implantation failure, “a Cu-IUD was inserted immediately after hysteroscopy and removed after two menstrual periods before embryo implantation” achieved a ”significantly higher implantation rate … and clinical pregnancy rate (45.13% vs. 26.44%) than the non-IUD group” (abstract (emphasis added)). Matsubayashi (Matsubayashi, H., et al., Is a high serum copper concentration a risk factor for implantation failure?, BMC Res Notes (2017) 10:387) examines the relationship between implantation (pregnancy) rates and serum copper concentrations including in Wilson’s disease patients, to report that “that high serum copper concentrations (high Cu/Zn ratio) are a risk factor for implantation failure” (abstract).
Applicant’s own disclosure states, “the discrepancy observed between the experimentation described herein showing a beneficial effect of copper on endometrial function (in terms of LIF/VEGF production) and the well described detrimental effect of copper on endometrial health and function in IUCD users, may be explained by the considerable difference in the "dose" of copper delivered to the endometrium” (Specification para.[0082] (emphasis added).) “[I]t is considered that the dose of copper required to elicit a beneficial endometrial response (i.e. an increase in LIF/VEGF) that can enhance embryo implantation must be below 13.3 μg, the lowest reported rate of copper released per day by an IUCD device capable of impairing implantation”. (Id. (emphasis added).)
As evidenced by the above-mentioned prior art, supplementation of copper in the uterine cavity could result in various outcomes in terms of embryo implantation, depending on the subject’s serum copper levels, stage in the menstrual cycle, and the dose administered, among others.
d. Level of one of ordinary skill in the art: the level of ordinary skill is high as physicians trained in assisted reproductive technology would practice administration of coper to a subject’s uterus in an amount “effective to stimulate endometrial production of leukaemia inhibitory factor (LIF) and/or vascular endothelial growth factor (VEGF)”.
e. Level of predictability in the art: the level of predictability in increasing embryo implantation by intrauterine copper administration would be low due to the variable and conflicting results depending on a patient’s individual fertility, and the doses and form used, among other factors.
f. Amount of direction provided by the inventor: Applicant does not appear to disclose guidance or methods of how to clinically enhance embryo implantation as in claim 66, i.e., in any subject, regardless of the subject’s pregnancy history or the stage in a menstrual cycle, comprising administering to the uterine cavity of the subject any solution, foam, or gel formulation comprising copper, in any amount effective to stimulate endometrial production of leukaemia inhibitory factor (LIF) and/or vascular endothelial growth factor (VEGF). Only a prophetic Example 3 is provided.
g. Existence of working examples: The disclosure includes animal models and in vitro data tending to support increased rate of embryo implantation based on production of LIF and VEGF, from copper chloride, in cultures of the human Ishikawa endometrial adenocarcinoma cell line (Figs.1A-B, 2A-B, 5A-B, 7A-C, 8A-B, and accompanying text). LIF and VEGF are known to support endometrial receptivity and embryo development which would enhance implantation rate. Murine embryo implantation outgrowth was shown (Figs.7A-C, 8A-B, and accompanying text). However no data specifically concerns different subject groups based on serum copper levels, prior pregnancies, etc., or timing of the copper administration relative to the menstrual cycle. Furthermore the guidance in the disclosure at paragraph [0082] is not recited in the present claims. Claims 67-69 recite dosage, however claim 66 are directed to subjects at large.
h. Quantity or experimentation needed to make or use the invention based on the content of the disclosure: considering the state of the art as discussed by the references above, particularly regarding the unpredictability of the subject’s and the embryo’s response to supplemental copper in the uterus, the person of ordinary skill would have to engage in significant amount experimentation and ingenuity to practice the invention commensurate in the scope of the claims.
In conclusion, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with claims 66-77.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries 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) 85 is rejected under 35 U.S.C. 103 as being unpatentable over Chwalibog (Mroczek-Sosnowska, N., et al., Nanoparticles of Copper Stimulate Angiogenesis at Systemic and Molecular Level, Int. J. Mol. Sci. 2015, 16, 4838-4849) in view of Mao (Mao, X., et al., Short-term copper intrauterine device placement improves the implantation and pregnancy rates in women with repeated implantation failure, Fertility and Sterility, 108, 55-61 (2017); see IDS).
Chwalibog reports stimulating angiogenesis by injecting a CuSO4 solution or a hydrocolloid of copper nanoparticles (NanoCu) in a chick embryo model (see entire document including title; abstract; p.4843 last para.; p.4845 4.1. Experimental Design). NanoCu exhibited pro-angiogenic properties at the systemic level, to a greater degree than CuSO4 salt (abstract).
Chwalibog does not specifically teach stimulating endometrial angiogenesis by administering copper to the uterine cavity as in claim 85.
Mao teaches that short-term copper intrauterine device placement (Cu-IUD) improves pregnancy rates among women with repeated implantation failure. The copper-containing device “continually release copper ions, which further alters the uterine inflammatory cytokine profiles” (p.60 right col. second para.). Proinflammatory “factors help the embryo adhere to the endometrium while also stimulating cells of the nutrient layer to invade the endometrium and give rise to blood vessels, ensuring blood supply to the embryo” (p.60 right col. first para.).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date to combine the teachings of Chwalibog and Mao and inject copper sulfate solution of copper nanoparticle hydrocolloid of Chwalibog to promote endometrial angiogenesis as recited in the instant claim 85. The skilled person would have been motivated to do so because both are drawn to administering copper to promote angiogenesis to support embryo development, and Mao teaches that intrauterine administration of copper is effective for endometrial angiogenesis.
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 66-77 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, 6, 8, 9, and 11-14 of U.S. Patent No. 12144824.
Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets are drawn to a method of enhancing embryo implantation in a subject, wherein the method comprises administering to a uterine cavity of the subject a formulation comprising copper, wherein the copper is provided in solution or gel form, and wherein the formulation is administered to the uterine cavity of the subject in an amount effective to stimulate endometrial production of leukaemia inhibitory factor (LIF) and vascular endothelial growth factor (VEGF). The ‘824 patent’s claims further recite “wherein the copper is provided to the uterine fluid cavity for a period no longer than 60 minutes” and therefore the claims anticipate the current claims.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to H. S. PARK whose telephone number is (571)270-5258. The examiner can normally be reached on weekdays.
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/H. SARAH PARK/Primary Examiner, Art Unit 1614
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