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 .
Election/Restrictions
Applicant’s election without traverse of Group I, presently claims 1-38 in the reply filed on 8/25/2025 is acknowledged.
Applicant’s species election without traverse of testicular organoids in the reply filed on 8/25/2025 is acknowledged.
Claims 39-51 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim.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 8/25/2025.
Claims 1-38 are under consideration on the merits and are being considered to the extent they read on the elected species.
Priority
When applicant files a continuation-in-part whose claims are not supported by the parent application, the effective filing date is the filing date of the child CIP. Any prior art disclosing the invention or an obvious variant thereof having a critical reference date more than 1 year prior to the filing date of the child will bar the issuance of a patent under 35 U.S.C. 102(b). See Paperless Accounting v. Bay Area Rapid Transit System, 804 F.2d 659, 665, 231 USPQ 649, 653 (Fed. Cir. 1986), and M.P.E.P. § 2133.01. This application is a continuation-in-part of Application 17/677,202 and a continuation of 14/718,390.
The claims under examination in the instant application are drawn to NEW methods of pre-treating the subject with a chorionic gonadotrophin (CG); administering a therapeutically effective amount of the gonadal organoids to the subject; and administering the CG to the subject to maintain LHCG receptor expression and signaling, the CG being administered periodically over time to cause a fluctuation of a concentration of the CG in the subject, or the CG being administered at a constant low CG concentration. It is noted for the record that Application 14/718,390 and 17/677,202 are silent entirely on claimed subject matter. As such, the claims under examination do not find basis in the claimed priority document.
For prior art purposes, therefore, the effective filing date for the claims currently under examination is the filing date of the instant application, i.e. February 22nd, 2022.
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 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 1-38 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 “low” in claims 1 and 20, ”periodically” in claims 1, 3, 5, 7, 20, 22, 24, and 26, and “slow” in claims 19 and 38 are relative terms which renders the claims indefinite. The terms “low”, “periodically”, and “slow” are not defined by the claims, 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. Clarification and/or correction is required.
Regarding claim 38, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
In so much that claims 2-19 and 21-38 depend from either claims 1 or 20 and do not resolve the point of confusion, these claims must be rejected with claims 1 and 20 as indefinite.
Claims 9, 10, 17, 18, 28, 29, 36, and 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.
In this case, claims 9 and 28 depend from claims 8 and 27 respectively, and recite “growing cells isolated from bone marrow or umbilical cord…” and generic culture media. However, claims 8 and 27 are already limited to just mesenchymal stem cells obtained from adults or umbilical cord, and “bone marrow” does not define the age of the subjects from which the mesenchymal stem cells are obtained. Therefore, claims 9 and 28 broaden the scope of the claims from which they depend and so fail to further limit the subject matter of the claim upon which they depend.
Claims 9-10 depend from claim 8, claims 17-18 depend from claim 16, claims 28-29 depend from claim 27, and claims 36 and 37 depend from claim 35 and all of which recite generic media. However, claims 8, 16, 27, and 35 are already limited to “CDM-3.4 differentiation media” which has a clear lexicographic definition at ¶0133. Therefore, claims 9, 10, 17, 18, 28, 29, 36, and 37 broaden the scope of the claims from which they depend and so fail to further limit the subject matter of the claim upon which they depend.
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.
Claims 1-7, 11-15, 20-26, and 30-34 are rejected under 35 U.S.C. 103 as being unpatentable over Sun et al. (Asian Journal of Andrology (2009), v11, p405-109; provided in the IDS dated 1/19/2024) in view of Pendergraft et al. (Biology of Reproduction, 2017, 96(3), 720–732; Reference U), Cruz-Acuna et al. (US 2020/0078493; Reference A), and Babek et al. (Curr Urol 2017;11:92–96; Reference V).
Sun teaches a method of transplanting Leydig cells into the testicular albuginea of surgically castrated prepubertal rats wherein said transplantation restores serum testosterone levels to levels comparable to sexually mature males (Abstract; p406, subheadings 2.1-2.4 for detailed methods; Fig. 1, groups E and F), reading in part on claims 1 and 20. Sun teaches measuring serum testosterone levels in the Leydig cell transplant recipients confirming increase serum testosterone levels as compared to untreated control subjects (p407, subheadings 3.1 and 3.2 and Fig. 1), reading in-part on claims 1 and 20. Sun teaches that that mature Leydig cell transplantation in prepubertal hypogonadism recipients has therapeutic potential in rats and merits further investigation for clinical application in humans (Abstract and p408, paragraph starting “Transplanted Leydig cells are a plausible substitute….”), reading in-part on claims 1 and 20.
Regarding claims 1 and 20, Sun does not teach administering any therapeutically effective amount of the elected species of testicular organoids to subject(s). Regarding claims 1 and 20, Sun does not teach pre-treating the subjects with a chorionic gonadotrophin (i.e. CG). Regarding claims 2-7 and 21-26, Sun does not teach any particular treatment schedule of administering the chorionic gonadotrophin to the subjects. Regarding claims 11 and 30, Sun does not teach human chorionic gonadotrophin. Regarding claims 12 and 31, Sun does not teach the embodiment of human chorionic gonadotrophin for the claimed animal-specific chorionic gonadotrophin. Regarding claims 13-15 and 32-34, Sun does not teach any claimed concentration ranges of chorionic gonadotrophin.
Pendergraft teaches testicular organoids obtained from human subjects, made by decellularizing adult testicular tissue and then repopulating the decellularized testicular tissue with spermatogonial stem cells (SSC), Leydig cells, and Sertoli cells (1st three subheadings of the Materials and Methods on p721-722), reading in-part on claims 1 and 20. Pendergraft teaches that the testicular organoids are capable of producing testosterone in vitro and respond to hCG stimulation (i.e. 2 nM hCG for 3 hours) with increased testosterone production (Fig. 3D, and the paragraph starting “To evaluate androgen production from …” on p728; the paragraph spanning p722-723), reading in-part on claims 1 and 20. Pendergraft teaches that the overall efficiency and success of spermatogenesis (in the mammalian testes) relies heavily on the presence of the Sertoli cell–spermatogonial stem cell (SSC) niche (1st paragraph of the Introduction on p721), reading in-part on claims 1 and 20
Cruz-Acuna teaches hydrogel compositions combined with testicular organoid(s) (¶0041), for administration to subjects in need thereof (¶0049-0051), reading in-part on claims 1 and 20.
Babek teaches administering human chorionic gonadotrophin (i.e. hCG) to subjects with varicocele and infertility undergoing varicocelectomy (Abstract), reading in-part on claims 1-7, 11, 12, 20-16, 30, and 31. Babek teaches that administering hCG dosage of 5,000 international units every week for 3 months starting one week after surgery improved the fertility of the hCG-treated subjects (Abstract and subheading “Subjects and Procedures” on p93), reading in-part on the pre-treatment with CG of claims 1 and 20, reading in-part on the CG timing of claims 2-7 and 21-26, reading on the human chorionic gonadotrophin of claims 11, 12, 30, and 31, reading on the CG dose range for claims 13 and 31, and reading in-part on the CG dose range for claims 14, 15, 33, and 34.
Regarding the elected species of testicular organoids for claims 1 and 20, it would have been obvious to a person of ordinary skill in the art before the invention was filed to substitute the Leydig cells of Sun with the testicular organoids of Pendergraft in Sun’s treatment methods in view of Cruz-Acuna. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because the Pendergraft teaches detailed methods of making testicular organoids, Pendergraft’s testicular organoids comprise Leydig cells which are taught by Sun as directly therapeutic in subjects suffering from prepubertal hypogonadism. The skilled artisan would have been motivated to do so because Cruz-Acuna teaches that persons of ordinary skill in this art contemplated administering testicular organoids to subjects in need thereof and because Pendergraft teaches that the overall efficiency and success of spermatogenesis (in the mammalian testes) relies heavily on the presence of the Sertoli cell–spermatogonial stem cell (SSC) niche, and so the substitution would likely improve upon the methods of Sun by further administering the other testicular cell types responsible for overall testicular function and spermatogenesis.
Regarding the chorionic gonadotrophin claims 1 and 20 and the chorionic gonadotrophin dose of claims 13 and 32, it would have been obvious to a person of ordinary skill in the art before the invention was filed to further add the hCG of Babek at the 5,000 I.U. dosage and treatment schedule of Babek to the methods of Sun. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Sun and Babek are broadly directed towards treating male subjects suffering from fertility disorders and in need thereof, and because Pendergraft teaches that contacting testicular organoids in vitro with hCG increases testosterone production from said organoids. The skilled artisan would have been motivated to do so because Babek teaches that administering hCG dosage of 5,000 international units every week for 3 months starting one week after surgery improved the fertility of the hCG-treated subjects, and so the addition would likely improve upon the treatment methods of Sun in treating prepubertal hypogonadism by improving the testosterone production in Sun’s subjects.
Regarding CG the pre-treatment of claims 1 and 20 and the CG dosage timing of claims 2-7 and 21-26, and the CG dosage ranges of claims 14, 15, 33, and 34, dosages are results-effective variables which can be optimized. In the case of administering CG, one of skill in the art would clearly recognize that doses must be timed sufficiently to maintain the efficacy of the drug in vivo and that the timing of dosages can be variable and could easily be optimized by a treating physician based on the needs and physiology of the individual patient. Babek clearly teaches that the hCG dose and timing of administration are known results-effective variables, as administering as hCG dose of 5,000 international units every week for 3 months starting one week after surgery improved the fertility of the hCG-treated subjects. As such and absent any showing of criticality, the concentration of CG and the timing of the dosages would amount to nothing more than routine experimentation that can be optimized on an individual patient basis (see In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977; and In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980)).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claims 19 and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Sun, Pendergraft, Cruz-Acuna, and Babek as applied to claims 1 and 20 above, and further in view of Wolf et al. (US 2004/0157951; Reference B) and Pawar et al. (International Journal of Pharmaceutics 611 (epub Nov. 23rd, 2021), 121312, 10 pages; Reference W).
The teachings of Sun, Pendergraft, Cruz-Acuna, and Babek are relied upon as set forth above.
Regarding claims 19 and 38, Sun, Pendergraft, Cruz-Acuna, and Babek do not teach implanting a slow-release device in the subject, the slow-release device being configured to administer the CG to the subject for 2-5 weeks, wherein the slow-release device is implanted one week prior to administering the therapeutically effective amount of the gonadal organoids to the subject to pre-administer the CG and the slow-release continues to administer the CG following administration of the gonadal organoids.
Wolf teaches implantable devices comprising a core and a permeable coating enclosing the core wherein the coating has a porosity that prevents components of the implant recipient's immune system from entering the core and further comprising a therapeutic substance (¶0003 and ¶0219), and preferably are microspheres (¶0136), reading in-part on claims 18 and 36. Wolf teaches implanting the implantable devices in immunoprivileged sites in a mammalian subject such as the testes where the host’s/subject’s immune response is least vigorous (¶0424-0425), reading in-part on claims 19 and 38.
Pawar teaches long-acting PLGA microspheres loaded with hCG (Abstract), reading in-part on claims 19 and 38. Pawar teaches that for male subjects, hCG is administered to induce spermatogenesis and pre-pubertal cryptorchism (the 1st paragraph of subheading 1 on the 1st page), reading on claims 19 and 38. Pawar teaches that subjects treated with long-acting PLGA microspheres loaded with hCG and administered subcutaneously maintains serum hCG levels for up to 13 days as compared to conventionally marketed injection formulation for hCG (subheading 3.12 on p9), reading on claims 19 and 38. Pawar teaches that the long-acting PLGA microspheres loaded with hCG would be advantageous to improve patient compliance by reducing the dosing frequency and serve as a promising approach in the treatment of infertility (subheading 4 on p9), reading on claims 19 and 38.
Regarding claims 19 and 38, it would have been obvious to a person of ordinary skill in the art before the invention was filed to further administer the long-acting PLGA microspheres loaded with hCG of Pawar to the subjects of Sun in Sun’s methods in view of Pendergraft and Babek. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because Sun is directed towards treating male subjects suffering from fertility disorders and in need thereof, Pawar teaches that hCG is typically administered to male subjects to induce spermatogenesis and pre-pubertal cryptorchism. The skilled artisan would have been motivated to do so because Pawar teaches that the long-acting PLGA microspheres loaded with hCG would be advantageous to improve patient compliance by reducing the dosing frequency and serve as a promising approach in the treatment of infertility, and would thus predictably improve upon the treatment methods of Sun.
Regarding the CG dosage timing of claims 19 and 38, dosages are results-effective variables which can be optimized. In the case of administering CG, one of skill in the art would clearly recognize that doses must be timed sufficiently to maintain the efficacy of the drug in vivo and that the timing of dosages can be variable and could easily be optimized by a treating physician based on the needs and physiology of the individual patient. Babek clearly teaches that the hCG dose and timing of administration are known results-effective variables, as administering as hCG dose of 5,000 international units every week for 3 months starting one week after surgery improved the fertility of the hCG-treated subjects. As such and absent any showing of criticality, the release of CG from the implantable device for 2-5 weeks would amount to nothing more than routine experimentation that can be optimized on an individual patient basis (see In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977; and In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980)).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter:
For clarity of record, the plain meaning of “CDM-3.4 differentiation media” as recited in claims 8, 16, 27, and 35 is the clear lexicographic definition of the media and its constituent components at ¶0133 of the specification (See M.P.E.P. § 2111.01, and particularly subheading IV).
Therefore, the claimed culture media is necessarily limited to a culture media consisting of the following components and at the prescribed concentrations: DMEM/Fl2, HEPES, no phenol red, 1% bovine serum albumin, 1X Penicillin-Streptomyocin-Amphotericin,, 1X Glutamax, 1X insulin-transferrin-selenium solution luteinizing hormone (LH, 5 ng/mL), follicle-stimulating hormone (FSH, 10 ng/mL), thyroid hormone (1 nM), putrescine (100 μM), human insulin-like growth factor I (IGF-1, 70 ng/mL), human glial cell line-derived neurotrophic factor (GDNF, 40 ng/mL), retinoic acid (200 ng/mL ), smoothened agonist (SAG, 0.2 μM), 22R-hydroxycholesterol (5 μM), 8-bromoadenosine 3',5'-cyclic adenosine monophosphate (8-Br-cAMP, 0.1 mM), testosterone (10 nM) and platelet-derived growth factor AA (PDGF-AA, 20 ng/mL).
Regarding claims 8, 16, and 27, while differentiation of gonadal organoids from bone marrow-derived or umbilical cord-derived mesenchymal stem cells, or adipose-derived stem cells is broadly contemplated by Bhatia (US 2015/0017140; Reference C) (see ¶0010, ¶0011, and ¶0030), Bhatia is considered the closest prior art to these claims and does not teach “CDM-3.4 differentiation media” as defined by the instant Application. As such, it would not be obvious to a person of ordinary skill in the art to differentiate the bone marrow-derived, umbilical cord-derived mesenchymal stem cells, or adipose-derived stem cells of Bhatia with the claimed CDM-3.4 differentiation medium to generate gonadal organoids.
In so much that claims 9-10 depend from claim 8, claims 17-18 depend from claim 16, claims 28-29 depend from claim 27, and claims 36-37 depend from claim 35, these claims incorporate the allowable subject matter of claims 8, 16, 27, and 35.
Conclusion
No claims are allowed.
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/Sean C. Barron/Primary Examiner, Art Unit 1653