DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 8/25/2025 has been entered.
Response to Amendments
Applicant's amendments filed 8/25/2025 to claims 1-4, 9, 11-15, and 20-23 have been entered. Claims 5 and 16 are canceled. Claims 1-4, 6-15, and 17-23 remain pending, and are being considered on their merits and to the extent they read on the elected species of menopause. References not included with this Office action can be found in a prior action. Any rejections of record not particularly addressed below are withdrawn in light of the claim amendments and/or applicant’s comments.
Affidavit/Declaration
The Declaration under 37 CFR 1.132 filed 9/02/2025 is insufficient to overcome the rejection of claims 1-4, 6-15, and 17-23 under 35 U.S.C. § 112(a) as set forth in the last Office action because: the instant Declaration includes statements which amount to an affirmation that the claimed subject matter functions as it was intended to function. This is not relevant to the issue of scope of enablement of the claimed subject matter and provides no objective evidence thereof that the claims are reasonable enabled to their full scope. See MPEP § 716. Furthermore, the instant Declaration refer(s) only to the methods described in the instant application and not to the individual claims of the application. Applicant substantially broadened the scope of the independent claims under consideration on the merits with the instant reply, and so there is no showing that the objective evidence of nonobviousness is commensurate in scope with the claims. See MPEP § 716.
It is noted for clarity of the record that the instant Declaration recites an incorrect Application number. This case is Application # 17/677,202.
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.
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 2-4, 9-15, and 17-23 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.
The term “normal” in claims 2-4, 9, and 12-15 is a relative term which renders the claim indefinite, because the claims or the claims from which these depend only recite generic “rebalancing of the hypothalamic-pituitary-gonadal (HPG) axis” which does not set forth any particular disease condition in the claimed subjects. The term “normal” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Correction is required.
Because claims 11, 12, and 17-23 depend from either claim 9 or claim 12 and do not resolve the point of confusion, these claims must be rejected with claim 9 as indefinite.
Claims 1-4, 6-15, and 17-23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification in view of the art set forth below is enabling for donor cells and effective dosages consisting of 1) the combination of autologous reprogrammed pluripotent stem cells, pluripotent germ cells, and oocytes for the treatment of menopause in female subjects for claims 1 and 9, and 2) induced pluripotent stem cells or Leydig cells for the treatment of andropause in male subjects for claims 1 and 9, does not reasonably provide enablement for the combination of cells including granulosa cells, myoid cells, thecal cells, and macrophages at any effective dosages to treat symptoms for the embodiments of menopause or andropause such as to restore circulating reproductive hormones to a level corresponding to the levels of a normal (human) subject 18-35 years of age as required for claims 1 and 9, and for any generic methods of differentiating mesenchymal stem cells into any generic differentiated cell, and does not reasonably set forth at any effective dosages of said generic differentiated cells to treat symptoms for the embodiments of menopause or andropause such as to restore circulating reproductive hormones to a level corresponding to the levels of a normal (human) subject 18-35 years of age as required for claim 12. 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.
It is noted that the broadest reasonable interpretation of the scope of claims 1 and 9 requires all of the recited cell types, and claim 12 is directed towards generic cells differentiated from mesenchymal stem cells. See M.P.E.P. § 2111.
The factors to be considered in determining whether undue experimentation is required are summarized in In re Wands, 858 F.2d 731, 737, 8 USPQd 1400, 1404 (Fed. Cir. 1988) (a) the breadth of the claims; (b) the nature of the invention; (c) the state of the prior art; (d) the level of one of ordinary skill; (e) the level of predictability in the art; (f) the amount of direction provided by the inventor; (g) the existence of working examples; and (h) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. While all of these factors are considered, a sufficient number are discussed below so as to create a prima facie case.
For clarity of record, the broadest reasonable interpretation of the scope of claim 1 requires all five cells types set forth in the claim. See M.P.E.P. § 2111.
Before the invention was filed, “menopause” was understood and defined by skilled artisans as the permanent cessation of menstruation resulting from the loss of ovarian follicular activity and is said to have occurred when there is one year without a menstrual period. See Hunter et al. (Best Practice & Research Clinical Obstetrics and Gynaecology (2007), 21(2) 261-274) (p262, 1st paragraph under “Definitions”). Hunter teaches that the main oestrogen, oestradiol, is produced during the reproductive years, and after the menopause oestrone becomes the main estrogen produced in small quantities and converted from androgens produced by the ovaries (p263, subheading “Biological Perspectives”, 1st paragraph). Hunter teaches that testosterone levels stay at approximately the same level after menopause (p263, subheading “Biological Perspectives”, 1st paragraph). Hunter teaches that hormone replacement therapy (HRT) is an effective treatment for the hot flashes and night sweat symptoms of menopause (p269, subheading “Treatments”, second paragraph).
Before the invention was filed, “andropause” was understood and defined by skilled artisans as synonymous for male hypogonadism and cause by low circulating levels of testosterone with clinical symptoms such as diminished erectile quality (particularly nocturnal erections), decreased libido, higher difficulty for achieving orgasms and reduced penis sensation. See Samaras et al. (European Geriatric Medicine 3 (2012) 368–373; Reference U) at subheadings 1 and 4.1.
Abuljadayel (US 2011/0091433) teaches methods of infusing a menopausal patient with a composition comprising autologous reprogrammed pluripotent stem cells, pluripotent germ cells, and oocytes, such as to increase the levels of IGF-1, esterdiaol (sic; likely a typo for estradiol) and LDL in the subject (¶0228 and Table 16). However, Abuljadayel does not teach administer granulosa cells, myoid cells, thecal cells, and macrophages either alone, in-combination with each other, or with the stem cells and/or oocytes to any menopausal subject. Abuljadayel envisions therapeutically effective dosages of 1x105-7 cells per kg (¶0131).
Takehara (Laboratory Investigation (published online November 19th, 2012), 93, 181-193) teaches that transplanted adipose-derived stem cells (ADSCs) administered to subjects having damaged ovaries differentiate into fibroblast-like cells in the thecal cell layer, not into granulosa and thecal cells to restore ovarian function as measured by cytokine expression (Fig. 6; paragraph starting “The measurement of….” on p189 through paragraph ending “…associated with follicular growth.” on p190).
Sun (Asian Journal of Andrology (2009), v11, p405-109; provided in the IDS dated 1/19/2024) teaches that administration of an effective dosage of Leydig cells (i.e. somatic cells of the interstitial tissue of the testes which produce testosterone) restores androgen production in an animal model of hypogonadism (Abstract). However, Sun does not teach administration of any other species of germ cell, and does not teach the Leydig cells administered in combination with granulosa, myoid, and thecal cells and macrophages.
Durruthy et al. (Human Molecular Genetics (epub. Jan. 2014), v23(12), p3071-3084; provided in the IDS dated 1/19/2024) teaches methods of transplanting human induced pluripotent stem cells (OSKMV) to the seminiferous tubules of germ-cell depleted male mice, wherein said stem cells produce prospermatogonia and/or spermatogonia cells in the testes of the subjects (Abstract; Fig. 3; p3075, 1st paragraph; p3077, right column, paragraph starting “In order to further verify…”; Fig. 5 “iPSC" panels; Fig 7 for a general schematic).
As can be seen from the cited art, the claimed methods of administering the combination of the embodiment of generic germ cells, granulosa cells, myoid cells, thecal cells, and macrophage cells to treat menopause and/or andropause in subjects at any therapeutically effective dosage as set forth in claim 1, granulosa and thecal cells and macrophages for claim 9, and generic differentiated cells for claim 12 would be unpredictable. Claims 1 and 9 recite in-part the combination of male gonadal cells (i.e. myoid cells) and female gonadal cells (granulosa and thecal cells), and non-reproductive cells (i.e. macrophages) as a species of immune cell and claim 12 is entirely directed towards generic differentiated cells, but in view of the cited art there is no reasonable expectation of success that the claimed cells would be capable of alleviating symptoms of menopause and/or andropause either by directly or indirect increasing estrogen and/or testosterone levels in a subject respectively. The prior art does not appear to contemplate administration of these cell types to subjects suffering from menopause and/or andropause and so does not teach any effective dosage such that the generic hormones of a subject would otherwise could be predictably restored to those of a comparably normal subject of 18-35 years of age.
Regarding the embodiment of menopause, the granulosa cells and thecal cells of claim 1 and the generic differentiated cells of claim 12, Abuljadayel is likely the closest prior art but only teaches oocytes in combination with stem and progenitor cells and does not teach any effective dosage of oocytes in combination with the other claimed cell types and does not provide any reasonable expectation of success to remove the stem cells. Takehara teaches that stem cells administered to subjects having damaged ovaries do not differentiate into granulosa and/or thecal cells such as to provide any reasonable expectation of success that administration granulosa and/or thecal cells would be capable of treating symptoms of menopause as encompassed by the scope of the claims. Furthermore, Abuljadayel and Takehara do not teach any therapeutically effective dosage of the claimed combination generic germ cells, granulosa cells, myoid cells, thecal cells, and macrophage cells.
Regarding the embodiment of andropause, Sun and Durruthy are likely the closest prior art but only teach administration of Leydig cells (i.e. a species of somatic cell) and induced pluripotent stem cells, neither of which are claimed nor encompassed by the scope of the claims. As such, neither Sun nor Durruthy do not provide a provide any reasonable expectation of success that administration of generic germ cells, granulosa and thecal cells, and macrophages would be capable of treating symptoms of andropause as encompassed by the scope of the claims. Furthermore, Abuljadayel and Takehara do not teach any therapeutically effective dosage of the claimed combination generic germ cells, granulosa cells, myoid cells, thecal cells, and macrophage cells.
In the unpredictable arts, more guidance is needed to satisfy the enablement requirement, see M.P.E.P. § 2164.03 and In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 927 F.2d 1200, 1212, 18 USPQ2d 1016, 1026 (Fed. Cir.), cert. denied, 502 U.S. 856 (1991). Also see M.P.E.P. § 2164.03. In this case regarding claims 1, 9, and 12, the working examples original disclosure is limited to methods of differentiating multipotent or pluripotent stem cell types into male gonadal cells for the treatment of andropause. (Examples 1-4 and 7). Any treatment of menopause at all is hypothetical (e.g. ¶0071), and there is no specific guidance to treat menopausal subjects with the claimed cell types at any effective dosage and treatment schedule such that the hormones of a subject would otherwise could be predictably restored to those of a comparably normal subject of 18-35 years of age and such guidance is not reasonably provided by the art prior to the filing of the instant application. Regarding the embodiment of andropause, there is no specific guidance to treat andropausal subjects with the claimed cell types at any effective dosage and treatment schedule such that the hormones of a subject would otherwise could be predictably restored to those of a comparably normal subject of 18-35 years of age and such guidance is not reasonably provided by the art prior to the filing of the instant application.
Dependent claims 2-4, 6-8, 10, 11, and 13-15 and 17-23 suffer from the same lack of enablement as their respective independent claims, as none of the dependent claims recite any effective dosage and treatment schedule and there is no evidence in the specification of operably treating a subject for menopause or andropause. Given the lack of predictability in this art and the lack of guidance in the specification, the quantity of experimentation must be held as undue because a person skilled in this art would be left to test every possible combination of cell concentrations and treatment schedules without any a priori reasonable expectation of success that any particular combination of cell dosage and treatment schedule would be operable and capable of restoring the hormone ratios in a subject suffering from menopause to correspond to a normal subject of 18-35 years of age. See M.P.E.P. § 2164.08(b).
Also see Rasmusson v. SmithKline Beecham Corp., 413 F.3d 1318 (Fed. Cir. 2005). "If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to ‘inventions' consisting of little more than respectable guesses as to the likelihood of their success. When one of the guesses later proved true, the ‘inventor’ would be rewarded the spoils instead of the party who demonstrated that the method actually worked. That scenario is not consistent with the statutory requirement that the inventor enable an invention rather than merely proposing an unproved hypothesis." See Rasmusson at 1325. And M.P.E.P. § 2164.05(a). In this case, enablement of a treatment method may be established either by including within the specification working embodiments or scientifically sound reasoning that would have led a skilled artisan at the time of filing to conclude that the method was enabled. However, both are absent in the instant prosecution for methods of claims 1-15 and 17-20 for the reasons given above and the claims are only enabled by the prior art teachings of Abuljadayel to the embodiment of treating menopause in subjects by administering an effective dosage of autologous reprogrammed pluripotent stem cells, pluripotent germ cells, and oocytes.
Therefore, the claims are rejected under 35 U.S.C. § 112(a) for lacking enablement for the full scope of the claims.
Response to Arguments
Applicant's arguments on pages 6-8 of the reply have been fully considered, but not found persuasive of error for the reasons given below.
On pages 6-8 of the reply, Applicant alleges that the claimed invention is adequately enabled. This is not found persuasive of error for several reasons. First, the instant amendments to claim 1 broaden the scope of the claims and do not exclude the elected invention of treating menopause. Second, none of Applicant’s arguments address the specific points of the now-modified scope of enablement rejection of record, briefly summarized as 1) the claimed methods of administering the combination of generic germ cells, granulosa cells, myoid cells, thecal cells, and macrophage cells to treat the embodiments of menopause or andropause in female and male subjects, respectively, at any therapeutically effective dosage as set forth in claim 1, granulosa and thecal cells and macrophages for claim 9, and generic differentiated cells for claim 12 would be unpredictable, and 2) any treatment of menopause at all is hypothetical (e.g. ¶0071) despite Applicant’s citation of other portions of the specification and other art and there is no specific guidance to treat menopausal or andropausal subjects with a subset of the claimed cell types at any effective dosage and treatment schedule such that the hormones of a subject would otherwise could be predictably restored to those of a comparably normal subject of 18-35 years of age.
The encompassed methods of treating subjects for menopause is only enabled for reprogrammed pluripotent stem cells, pluripotent germ cells, and oocytes by the teachings of Abuljadayel and Takehara and not by the instant specification, but the claims continue to recite granulosa cells, myoid cells, thecal cells, and macrophages for which there is a prima facie case for lack of enablement as set forth above. Similarly, the encompassed methods of treating subjects for andropause is only enabled for induced pluripotent stem cells and Leydig cells by the teachings of Sun and Durruthy and not by the instant specification, but the claims continue to recite generic germ cells, granulosa cells, myoid cells, thecal cells, and macrophages for which there is a prima facie case for lack of enablement as set forth above
The rejection of record is a scope of enablement rejection, and so the claims recite a combination of enabled and non-enabled subject matter. Removal of the non-enabled subject matter (i.e. removal of granulosa cells, myoid cells, thecal cells, and macrophages and narrowing to treatment of menopause) would likely advance prosecution of the case. It is noted that narrowing the claims to treatment of andropause would likely require careful reconsideration of Sun and Durruthy as prior art under 35 U.S.C. § 103 and an updated search, and non-statutory double patenting relative to US Application # 14/718,390 (presently US Patent # 11,253,549).
Applicant’s remarks on page 8 regarding a Declaration in the parent case are acknowledged, but are still not found persuasive because Affidavits or declarations, such as those submitted under 37 CFR 1.130, 1.131 and 1.132, filed during the prosecution of the prior application do not automatically become a part of this application. Where it is desired to rely on an earlier-filed affidavit or declaration, the applicant should make the remarks of record in this application and include a copy of the original affidavit or declaration filed in the prior application. However, the claims of the parent case are directed towards treating andropause which is not presently claimed a and so the Declaration would not likely be commensurate to the claimed methods which were amended in the instant reply to broaden the claims to rebalancing/treating generic HPG axis conditions in subjects.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Miyamoto et al. (US 7,879,603; Reference A), for methods of differentiating mesenchymal stem cells into hormonre-secreting cells.
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/Sean C. Barron/Primary Examiner, Art Unit 1653