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 .
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 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.
DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 Apr. 4, 14, 2026 has been entered. All arguments, amendments, the IDS submitted on Apr. 4, 14, 2026 and the Declaration submitted under 37 C.F.R. §1.132 by Christian Kramme, Ph.D. have been fully considered.
Status of the Claims
Claims 21, 22, 35, 37, 39-41, 43, 55, 57, and 61-71 are currently pending.
Claim 21 is amended.
Claims 1-20, 23-34, 36, 38, 42, 44-54, 56, and 58-60 are cancelled.
Claims 21, 22, 35, 37, 39-41, 43, 55, 57, and 61-71 have been considered on the merits.
Claim Rejections - 35 USC § 112
The claim rejections under 35 USC § 112, (b) or second paragraph (pre-AIA ), are withdrawn due to amendment.
Claim Rejections - 35 USC § 103
The claim rejections under 35 USC § 103 are revised due to reconsideration and amendment.
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.
Claims 21, 22, 35, 37, and 39-41 are rejected under 35 U.S.C. 103 as being unpatentable over Tilly et al. (US 2016/0237402 A1) (ref. of record).
With respect to claims 21 and 22, Tilly teaches a method of maturing immature oocytes to produce a mature oocyte ex vivo (abstract, 0016, 0018, 0027 and 0032). With respect to step (ii) of claim 21 and claim 22, Tilly teaches co-culturing the immature oocytes with a population of “synthetic” granulosa cells generated from exogenous stem cells (abstract, 0005, 0016, 0023, 0093 and 0096). Tilly teaches that the multipotent cell used to generate the granulosa cells include human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (0093-0094).
Tilly does not explicitly teach where the immature oocytes are retrieved from the subject as recited in step (i) of claim 21 or previously retrieved as recited in claim 22 or where the immature oocytes are co-cultured ex vivo with the “synthetic” granulosa cells as recited in step (ii) of claim 21 and claim 22. However, Tilly teaches producing mature oocytes ex vivo for use in in vitro fertilization by co-culturing the “synthetic” granulosa cells with oocyte precursor cells and ovarian tissue which can have been previously frozen and stored (0032, 0099, 0100, and 109). Tilly teaches the method where mature oocytes are produced by combining the synthetic granulosa cells, oocyte precursor cells and ovarian tissues (0027) and teaches that “any known methods and suitable conditions for making ex vivo artificial ovarian environments or for the maturation of immature follicle sand oocytes to mature follicles and oocytes can be used” (0115). Accordingly, at effective time of filing of the claimed invention, one of the ordinary skill in the art would have been motivated to modify this teaching in Tilly to include co-culturing of immature oocytes for the benefit of producing mature oocytes. One of ordinary skill in the art would have had a reasonable expectation of success in making such a modification, since Tilly teaches that the “synthetic” granulosa cells for maturing oocytes ex vivo and the successful maturation of immature oocytes in vivo with the “synthetic” granulosa cells. Additionally, one of ordinary skill in the art would reasonably predict that at least at some point in time the ovarian tissue retrieved in Tilly would have to contain immature oocytes on the way to maturing the tissue. In support, Tilly teaches contacting the immature oocytes in the in vivo ovarian tissue with the synthetic granulosa cells (0096).
With respect to claims 21 and 22, Tilly teaches the method where the subject is undergoing infertility treatment, in vitro fertilization, or has been treated for cancer and has been subjected to cytotoxic therapies (0021). Therefore, the oocytes are retrieved from human subjects for use in an assisted reproduction technology. Even though, Tilly does teach that their method can be used in the manner instantly claimed for the use in an ART procedure as recited in claims 21 and 22, the preambles of claims 21 and 22 fail to limit the methods of the claimed inventions and the statement is considered statements of purpose or intended use of the corresponding inventions. “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction”. (MPEP 2111.02 Section II) In the instant case, the claim body describes a structurally complete invention in which the deletion of the preamble would not affect steps of the claimed invention.
With respect to claim 35, Tilly teaches that the immature oocytes are primary oocytes arrested prophase I (which is the same as the germinal vesicle stage) (0059).
With respect to claim 37, Tilly teaches the granulosa cells secrete ovarian derived hormones including estradiol (0022-0024).
Tilly is silent with respect to the number of granulosa cells used in the method and does not teach that the population of granulosa cells is about 50,000 to 500,000 cells as recited in claim 39. Although Tilly is silent with the number of cells in the co-culture and does not teach the range recited in claim 39, one of ordinary skill in the art would recognize that the number of granulosa cells in the co-culture is a result effective variable and that the number of granulosa cells in the co-culture would be matter of routine optimization based on factors such as the available granulosa cells and the number of oocytes being cultured.
With respect to claims 40 and 41, Tilly teaches the method where follicle stimulating hormone (FSH) is included during maturing the oocytes in vitro to form the mature follicle and the mature oocyte (0017 and 0025). Although, Tilly does not teach the amount of FSH present in the medium as 75 mIU/ml as recited in claim 41, one of ordinary skill in the art would recognize this as a result effective variable and would be matter of routine optimization since culture components are routinely adjusted and optimized in the art.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claim 35 is rejected under 35 U.S.C. 103(a) as being unpatentable over Tilly (as applied to claims 21, 22, 35, 37, and 39-41 above), and further in view of Combelles et al. (Human Reproduction, 2005) (ref. of record).
The teachings of Tilly can be found in the previous rejection above.
Tilly does not teach the method where the one or more immature oocytes are metaphase (MI)-stage oocytes as recited in claim 35.
However, Combelles teaches a similar method of maturing oocytes by co-culturing immature oocytes with cumulus cells to mature the oocytes in vitro by culturing in a three-dimensional system (abstract). Combelles further teaches the immature oocytes are germinal vesicle (GV)-stage or metaphase I (MI)-stage oocytes (pg. 1350 Col. 2 para. 3).
Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the method of Tilly so that the immature oocytes are metaphase I (MI)-stage oocytes for the benefit of preparing mature oocytes by co-culturing immature oocytes with ovarian support cells as taught by Combelles. It would have been obvious to one of ordinary skill in the art to modify Tilly so that the immature oocytes are metaphase (MI)-stage oocytes, since this is a known stage of immature oocytes which is known to be matured in culture as taught by Combelles. For these same reasons, one of ordinary skill in the art would have a reasonable expectation of success in modifying Tilly to include metaphase (MI)-stage oocytes in their method of preparing oocytes.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claim 43 is rejected under 35 U.S.C. 103(a) as being unpatentable over Tilly (as applied to claims 21, 22, 35, 37, and 39-41 above), and further in view of Obata et al. (US 2018/0251729 A1) (ref. of record).
The teachings of Tilly can be found in the previous rejection above.
Tilly does not teach the method where the oocytes are denuded following co-culturing as recited in claim 43.
However, Obata teaches a similar method of culturing oocytes-granulosa cell complexes to form functionally mature oocytes (abstract, 0010, and 0174-0175). Obata teaches dissociating cumulus cells from mature oocytes following co-culturing of the oocytes with ovarian support cells (denuding the oocytes or removing the cumulus cells from the oocytes) and then using the oocytes for in vitro fertilization (0176).
Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the method taught by Tilly so that the oocytes are denuded after co-culturing for the benefit of maturing the oocyte by keeping the cumulus cells in contact with the oocyte and then prepare the cells for in vitro fertilization as taught by Obata. It would have been obvious to one of ordinary skill in the art to modify the method taught by Tilly so the oocytes are denuded after co-culturing, since similar methods of maturating oocytes in vitro for IVF were known to co-culture oocytes with granulosa cells and then denude the cells after co-culturing but prior to in vitro fertilization as taught by Obata. Additionally, one of ordinary skill in the art would have had a reasonable expectation of success in making such a modification to the method taught by Tilly, since similar methods of maturing oocytes were known to denude the oocytes after co-culturing as taught by Obata.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 55, 57, 61-63, 65, and 67-71 are rejected under 35 U.S.C. 103(a) as being unpatentable over Tilly (as applied to claims 21, 22, 35, 37, and 39-41 above), and further in view of Fadini et al. (Reproductive Biomedicine Online, 2009) (ref. of record).
The teachings of Tilly can be found in the previous rejection above.
Tilly is silent with to whether the subject is administered one or more follicular stimulation agents during a follicular stimulation period as recited in claims 55 and 57. Similarly, Tilly does not teach the follicular stimulation period is from 2 to 5 days as recited in claim 67; and does not teach the method where the follicular stimulation period has a duration of 2 days, 3 days, 4 days or 5 days as recited in claims 68-71, respectively. Tilly does not teach the method where the follicular stimulation agents contain follicle stimulating hormone (FSH) as recited in claim 61 and where it is administered to the subject once daily as recited in claim 62. Tilly does not teach the method where the FSH is administered to the subject in a plurality of doses over the span of the follicular stimulation period, where each of the doses comprises from about 100 international units (IU) to about 200 IU of the FSH as recited in claim 63. Tilly does not teach the method where following the follicular stimulation period, the subject undergoes a coasting period during which time a follicular stimulation agent is not administered to the subject, optionally wherein the coasting period has a duration of from 1 day to 2 days as recited in claim 65.
However, Fadini teaches a method of preparing mature oocytes for use in an assisted reproduction technology in humans where the oocytes are matured in vitro (abstract and pg. 345 para. 2 to pg. 346 para. 3). With respect to claims 55, 57, 61-63, 67, and 69, Fadini teaches the method where the patients were administered 10,000 IU HCG; administered 150 IU/day FSH from day 3 of the cycle for three days; or administered 150 IU/day FSH from day 3 of their menstrual cycle plus 10,000 IU HCG (pg. 344 Col. 2 para. 3). Fadini further reports that FSH priming or HCG priming alone did not show any significant effect on clinical outcome, however the short course of FSH plus HCG was efficient for a mild stimulation in healthy patients (pg. 348 last para. and pg. 350 last para.). In addition, with respect to claim 65, Fadini teaches the subject where they undergo a coasting period where the follicular stimulation agent is not administered for 24-48 hours (pg. 344 Col. 2 para. 5).
Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the method of Tilly to include subjects or patients which were administered one or more follicular stimulation agents including FSH at the claim doses for a follicular stimulation from 2 to 5 days and where they have undergone a coasting period for the benefit including additional patient populations as taught by Fadini. It would have been obvious to one of ordinary skill in the art to modify the method of Tilly to include subjects or patients which were administered one or more follicular stimulation agents, such as FSH, for a follicular stimulation from 2 to 5 days and with a coasting period, since such patients populations were known for preparing oocytes for assisted reproduction technology as taught by Fadini. Additionally, one of ordinary skill in the art would have had a reasonable expectation of success in making such a modification, since Fadini teaches such patient populations have successful clinical outcomes after in vitro maturation of retrieved oocytes.
Although, Fadini does teach the method where the follicular stimulation period has a duration of 2 days, 4 days or 5 days as recited in claims 68, 70 and 71, respectively, it would have been obvious to one of ordinary skill in the art to optimize the duration of the follicular stimulation period based on the patient as evidenced by Fadini (2013). Fadini (2013) discusses determining the appropriate length, hormones and amounts of hormones used to prime different patient types for IVM (in vitro maturation) (pg. 1163-1165).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claim 64 is rejected under 35 U.S.C. 103(a) as being unpatentable over Tilly in further view of Fadini (as applied to claims 21, 22, 35, 37, 39-41, 55, 57, 61-63, 65, and 67-71 above), and in further in view of Hofmann et al. (Journal of in vitro Fertilization and Embryo Transfer, 1989) (ref. of record) as evidenced by Fatemi et al. (Reproductive Biology and Endocrinology, 2021) (ref. of record).
The teachings of Tilly and Fadini can be found in the previous rejection above.
Neither Tilly or Fadini teach the method where FSH is administered to the subject in an amount of from about 300 IU to about 600 IU per day, from about 300 IU to about 500 IU per day, or from about 300 IU to about 400 IU per day as recited in claim 64.
However, Hofmann teaches administering to a low-responder patients FSH in the amounts of 300 IU and 450 IU for ovarian stimulation for in vitro fertilization (pg. 286 Col. 1 para. 2). Hofmann teaches that raising and maintaining FSH levels during stimulation in low-responders reduced the number cancellations (stopping the stimulation procedure due to no ovary stimulation) and may improve in vitro fertilization outcomes (abstract).
Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would be motivated to modify the method taught by the combined teachings of teachings of Tilly and Fadini to administer FSH within the claimed dosages in order to adjust the amount administered depending on the patient and their response to FSH as taught by Hofmann. It would have been obvious to one of ordinary skill in the art to modify the method taught by the combined teachings of teachings of Tilly and Fadini so that the FSH amounts are adjusted for the patient and are at the amounts claimed, since Hofmann teaches administering to a low-responder patients FSH in the amounts of 300 IU and 450 IU for ovarian stimulation. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in making such a modification to the method taught by the combined teachings of teachings of Tilly and Fadini, since Hofmann teaches adjusting the amount of FSH administered and the higher doses within the ranges of claim 64.
Although Hofmann does not teach the exact ranges recited in claim 29, the ranges overlap significantly in claim 64 with the ranges taught. Furthermore, one of ordinary skill in the art would recognize that the amount of FSH administered during the follicular triggering period is a result effective variable and that the amount of FSH would be matter of routine optimization as evidenced by Fatemi. Fatemi reports that routine individualization of FSH dose is standard clinical practice during ovarian stimulation in patients undergoing assisted reproductive technology (abstract).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claim 66 is rejected under 35 U.S.C. 103(a) as being unpatentable over Tilly in further view of Fadini (as applied to claims 21, 22, 35, 37, 39-41, 55, 57, 61-63, 65, and 67-71 above), and in further in view of De Vos et al. (Journal of in vitro Fertilization and Embryo Transfer, 1989)(ref. of record).
The teachings of Tilly and Fadini can be found in the previous rejection above.
Neither Tilly or Fadini teach the method where (a) the subject is one that has completed oral contraceptive treatment within 28 days of commencement of the follicular stimulation period, and wherein the follicular stimulation period commences at least 5 days after cessation of the contraceptive treatment; or (b) the subject has not undergone oral contraceptive treatment within 28 days of commencement of the follicular stimulation period, and wherein the follicular stimulation period commences on day 2 of the subject's menstrual cycle as recited in claim 66.
De Vos teaches a method of preparing and maturing oocytes in vitro for artificial reproductive technology (abstract, pg. 860 para. 1, and pg. 861 para. 1). De Vos further teaches a follicular stimulation protocol where the follicular stimulation agent is started on day 2 or day 3 of the spontaneously menstruating patients (pg. 861 Col. 1 para. 2).
Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the method taught by the combined teachings of teachings of Tilly and Fadini to include subjects or patients who have not undergone oral contraceptive treatment within 28 days of commencement of the follicular stimulation period, and where the follicular stimulation period commences on day 2 of the subject's menstrual cycle for the benefit including additional patient populations as taught by De Vos. It would have been obvious to one of ordinary skill in the art to modify the method taught by the combined teachings of teachings of Tilly and Fadini to include subjects or patients which have not undergone oral contraceptive treatment within 28 days of commencement of the follicular stimulation period, and where the follicular stimulation period commences on day 2 of the subject's menstrual cycle, since such patients populations were known for preparing oocytes for assisted reproduction technology as taught by De Vos. Additionally, one of ordinary skill in the art would have had a reasonable expectation of success in making such a modification, since Fadini teaches such patient populations have successful clinical outcomes after in vitro maturation of retrieved oocytes.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed Apr. 14, 2026 have been fully considered but they are not persuasive.
With respect to the rejections under 35 U.S.C. §103, Applicant argues that Tilly does not represent the closest prior art, since Tilly is directed to solving a problem distinct from the claimed method. Specifically, Applicant argues that the claimed intention is directed to a method of maturing immature oocytes ex vivo by co-culturing with granulosa cells obtained from exogenous human induced pluripotent stem cells (hiPSCs) whereas Tilly is directed to oogenesis and folliculogenesis occurring in ovarian tissue (Remarks pg. 6 para. 4). However, this argument was not found to be persuasive, since Tilly clearly teaches a method of producing mature oocytes for a human subject for use in assisted reproduction technology (abstract, 0016, 0018, and 0021). The technical problem of Tilly appears to the same if not similar to the claimed invention.
Applicant argues that one of ordinary skill in the art would not expect the methods of Tilly to be relevant to the claimed method, given the biological differences between oocyte maturation ex vivo and within ovarian tissue (Remarks pg. 6 para. 4). However, this argument was not found to be persuasive, since Tilly teaches the ex vivo maturation of oocytes and the claimed method does not exclude the ex vivo use of ovarian tissue. 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”. MPEP 2111.03
Applicant argues that subsequent research has shown that the conclusions underlying Tilly’s disclosure are scientifically inaccurate making the Tilly non-enabled prior-art reference. Specifically, Applicant argues that DDX4-positive cells isolated in Tilly are perivascular somatic cells and not germline or oocyte precursor cells and this negates the cell-identity assumption on which Tilly’s ovarian development models depends (pg. 6-7 bridging para.). However, this argument was not found to be persuasive, since not all of Tilly’s conclusions are based on isolated DDX4-positive cells and the subsequent research does not definitively prove that Tilly’s disclosure is scientifically inaccurate. For instance, Tilly teaches producing mature oocytes ex vivo by combining synthetic granulosa cells, oocytes precursor cells and ovarian tissues which does not involve the isolation of oocyte precursor cells using DDX4 expression (0032). Additionally, Silvestris et al. (International Journal of Molecular Sciences, 2019) reports that Tilly standardized the FACS-based protocol for isolating ovarian stem cells (OSCs) using Ddx4 and that the cells obtained by this method were found to differentiate in vitro to mature oocytes (pg. 3 para. 2). Additionally, Silvestris reports by binding the Ddx4 molecule for immunomagnetic selection of ovarian cell suspension, they isolated cells OSCs as well (pg. 3 para. 3).
Applicant argues that Tilly is not the closest prior art, but that instead Combelles, Obata, and Fadini represent the closest prior art, since the references are directed to in vitro maturation (IVM) techniques and the same fundamental problem that instant claims seek to solve. Applicant further argues that all of these references rely on endogenous granulosa cells from the subject’s own cumulus-oocyte complex and none of these references teach exogenous granulosa cells and the claimed invention has surprising and beneficial improvements that are commensurate in scope with the subject matter of the instant claims (Remarks pg. 7 para. 2). However, these arguments were not found to be persuasive, since Tilly is also directed to a method of maturing oocytes for use in an assisted reproduction technology (0021) and would also be considered the closest prior art. It is maintained that Tilly teaches maturing immature oocytes using “synthetic” granulosa cells which include iPSC-derived granulosa cells (abstract, 0095-0096 and 0099). Tilley teaches that the “synthetic” granulosa cells are derived from multi-potent cells which include iPSC-derived granulosa cells in addition to embryonic stem cells, pluripotent stem cells, and very small embryonic-like cells (0005 and 0069).
Applicant argues that Tilly does not teach retrieving an immature oocyte that is in the germinal vesicle (GV) or metaphase (MI) stage, but instead teaches the manipulation of oocyte precursor cells, oogonial stem cells or in vitro-derived materials and the methods are performed in ovarian tissue (Remarks pg. 7-8 bridging para.). However, this argument was not found to be persuasive, since after further consideration it is noted that Tilly teaches the immature oocytes are primary oocytes that are arrested in prophase I (which are germinal vesicle (GV) stage oocytes) (0059). In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Combelles is being relied upon for the teaching of maturing immature oocytes that are metaphase I-staged oocytes. Applicant addressed each prior art reference separately and only with regard to the specific limitations of that reference. However, when the prior art references are taken as a whole, they teach that the skilled artisan knows each step of the method as currently claimed.
Applicant argues that para. 0016, 0032, 0096, 0099, 0100 and 0109 of Tilly demonstrate Tilly’s focus is on oocyte maturation and the presence of ovarian tissue in the method of maturing (Remarks pg. 8-9 bridging para.). However, this argument was not found to be persuasive, since the claim method does not exclude ovarian tissue and in these paragraphs synthetic granulosa cells are included along with ovarian tissue containing immature oocytes. As previously stated, 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”. MPEP 2111.03
Applicant argues that Tilly’s methodology is useful in the context of ovarian tissue and Tilly does not indicate their techniques are relevant for the maturation of a retrieved oocyte in an ex vivo environment lacking ovarian tissue (Remarks pg. 9 para. 2). Additionally, Applicant argues that Tilly fails to disclose the maturation of an oocyte in an ex vivo environment that is free of ovarian tissue and, instead Tilly is directed to solving a different biological problem than the claimed invention. Specifically, Applicant argues that Tilly is directed to promoting organ-wide ovarian development which includes the generation of ovarian follicles and maturation of oocytes within ovarian tissue. Applicant argues that these developmental processes are different from the claimed method directed to the ex vivo oocyte maturation in an environment that is free from ovarian tissue (Remarks pg. 9 para. 3). As evidence, Applicant refers to the Declaration submitted under 37 C.F.R. § 1.132 by Dr. Christian Kramme, who describes oocyte maturation in an ex vivo environment and the definition of an immature oocyte as being arrested at a particular stage of meiosis (germinal vesicle (GV) or metaphase (MI) stage) (Remarks pg. 9 para. 4 to pg. 10 para. 1). However, these arguments were not found to be persuasive, since the claimed method does not exclude the presence of ovarian tissue. Furthermore, Tilly teaches the immature oocytes are primary oocytes that are arrested in prophase I (which are germinal vesicle (GV) stage oocytes) (0059) and it is maintained that one of ordinary skill in the art would reasonably predict that at least at some point in time the ovarian tissue retrieved in Tilly would have to contain immature oocytes on the way to maturing the tissue. In further support, Tilly teaches contacting the immature oocytes in the in vivo ovarian tissue with the synthetic granulosa cells (0096). Accordingly, based on the teachings of Tilly, one of ordinary skill in the art would have had a reasonable expectation of success that the synthetic granulosa cells would mature immature oocytes ex vivo.
Applicant argues that the immature oocytes in Tilly are not a starting material to be matured ex vivo, but rather part of a system that recapitulates the ovarian environment requiring ovarian tissue. Applicant argues that Dr. Kramme explains that the factors influencing oocyte maturation ex vivo without ovarian tissue are distinct form factors that drive follicle development and oogenesis (Remarks pg. 10 para. 2). However, these arguments were not found to be persuasive, since claim 21 does not exclude additional elements or steps such as recapitulating the ovarian environment ex vivo. The claim requires the retrieving of one or more immature oocytes and does not specify whether the oocytes remain with ovarian tissue and which is made obvious by Tilly. Furthermore, 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”. MPEP 2111.03
Applicant argues that Tilly does not disclose any evidence that their methods would result in meiotic resumption and one of ordinary skill in art would have no reason to look to Tilly for guidance as to the maturation of an oocyte in an ex vivo setting that is free of ovarian tissue (Remarks pg. 10 para. 2). However, this argument was not found to be persuasive, since Tilly teaches their methods result in mature oocytes (0016 and 0115) and the claim does not require the ex vivo setting that is free of ovarian tissue. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., ex vivo setting that is free of ovarian tissue) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant argues that since Tilly is directed to a different technical problem, the tissue-based teachings of Tilly cannot be extrapolated to the claimed ex vivo IVM technique and does not provide one skilled in the art with a reasonable expectation of success (Remarks pg. 10 para. 3 and pg. 11 para. 4). However, this argument was not found to be persuasive, since, as stated previously, Tilly clearly teaches a method of producing mature oocytes for a human subject for use in assisted reproduction technology (abstract, 0016, 0018, and 0021). The technical problem of Tilly appears to the same if not similar to the claimed invention.
Applicant further argues that rejection fails, since the foundational biological premises of Tilly have been severely undermined by pre-priority date publication that call into question the veracity of Tilly’s conclusion and, therefore, Tilly cannot support a reasonable expectation of success and has diminish evidentiary weight (Remarks pg. 10 para. 3-4). Specifically, Applicant argues that DDX4-positive cells isolated in Tilly are perivascular somatic cells and not germline or oocyte precursor cells and this negates the cell-identity assumption on which Tilly’s ovarian development models depends (Remarks pg. 10 last para.). However, these arguments were not found to be persuasive, since as stated previously, not all of Tilly’s conclusions are based on isolated DDX4-positive cells and the subsequent research does not definitively prove that Tilly’s disclosure is scientifically inaccurate. For instance, Tilly teaches producing mature oocytes ex vivo by combining synthetic granulosa cells, oocytes precursor cells and ovarian tissues which does not involve the isolation of oocyte precursor cells using DDX4 expression (0032). For example, Silvestris et al. (International Journal of Molecular Sciences, 2019) reports that Tilly standardized the FACS-based protocol for isolating ovarian stem cells (OSCs) using Ddx4 and that the cells obtained by this method were found to differentiate in vitro to mature oocytes (pg. 3 para. 2). Additionally, Silvestris reports by binding the Ddx4 molecule for immunomagnetic selection of ovarian cell suspension, they isolated cells OSCs as well (pg. 3 para. 3).
Applicant argues that Tilly starts with a misidentified cell population and any downstream inferences made in Tilly are therefore flawed, since the conclusions are being made for the misidentified cells. The Applicant further argues that perivascular cells which Tilly uses and are misidentified as germline or oocyte precursor cells, do not possess meiotic competence and intrinsic development potential like germline or oocyte precursor cells (Remarks pg. 11 para. 1). However, these arguments were not found to be persuasive, since the method of Tilly does not require the isolation of specifically DDX4 positive cells even though in some of the examples DDX4 expression was used to show the presence of oogonial stem cells (OSCs). For instance, in Example 1, DDX4 expression was used to demonstrated the presence of OSCs in the ovaries of mice at advanced ages. Example 2 demonstrates the reduced capability of OSCs to differentiate into oocytes from advanced aged mice using transgenic reporter mice where the expression of green fluorescent protein (GFP) is driven by the promoter of the meiosis commitment gene. Example 3 demonstrates that the transplantation of juvenile ovarian tissue derived cells rescues oocyte and follicle formation in aged mice by counting oocytes. Example 4 shows that OSCs are present in the ovaries of peri- and post-menopausal women by DDX4 expression and that the DDX4 positive OSCs isolated from post-menopausal human ovaries still retained the capacity for oocyte formation ex vivo. Example 5 demonstrates that granulosa cells differentiated from multi-potent cells produce ovarian steroidal hormones and concludes that the synthetic granulosa of the present technology are useful for the ex vivo or in vivo formation of follicles, which assist in the production of mature follicles and oocytes. Example 6 shows granulosa cells derived from multi-potent cells migrate to immature oocytes and developing follicles in neo-natal ovaries, using an anti-Daz1 antibody and concludes that synthetic granulosa cells are useful for promoting the growth and maturation of follicles, follicle-like structures, and immature oocytes. Even if the staining of the cells for DDX4 expression to prove that there are OSCs present in advanced aged mice and humans is inaccurate, this does change or impact the method of maturing ex vivo immature oocytes from a subject and the supporting evidence that the synthetic granulosa cells are capable of promoting the growth and maturation of follicles, follicle-like structures, and immature oocytes.
Applicant argues that Wagner shows that DDX4 cells isolated using the same DDX4 antibody-based approach as Tilly are perivascular somatic cells rather than germline or oocyte precursor cells (Remarks pg. 11 para. 2). Additionally, Applicant argues that Yoshihara shows further support and expresses caution with relying on the DDX4-based isolation method developed by Tilly for isolating germline cells, since the method leads to the isolation of perivascular cells instead (Remarks pg. 11 para. 3). Applicant argues that that Wagner and Yoshihara confirm empirically that the cells relied upon in Tilly lack germline identity and meiotic competence (Remarks pg. 11 para. 4). However, this argument was not found to be persuasive, since even if the staining of the cells for DDX4 expression to prove that there are OSCs present in advanced aged mice and humans of Tilly is inaccurate, this does change or impact the method of maturing ex vivo immature oocytes from a subject and the supporting evidence that the synthetic granulosa cells are capable of promoting the growth and maturation of follicles, follicle-like structures, and immature oocytes as explained above. The controversy of whether or not DDX4 cells represent OSCs or perivascular cells does not invalidate the method of Tilly where synthetic granulosa cells derived from human iPSCs mature immature oocytes and precursors, since Tilly does not use the DDX4 expression data to prove this.
Applicant argues that Tilly is not the closest prior art, but that instead Combelles, Obata and Fadini represent the closest prior art, since the references are directed to in vitro maturation (IVM) techniques and the same fundamental problem that instant claims seek to solve. Applicant further argues that all of these references rely on endogenous granulosa cells from the subject’s own cumulus-oocyte complex and none of these references whereas the claimed invention has surprising and beneficial improvements that are commensurate in scope with the subject matter of the instant claims (Remarks pg. 11-12 bridging para.). However, this argument was not found to be persuasive, since Tilly clearly teaches a method of producing mature oocytes for a human subject for use in assisted reproduction technology (abstract, 0016, 0018, and 0021). The technical problem of Tilly appears to the same if not similar to the claimed invention.
Applicant argues that the reply submitted on Feb. 2, 2026, they provided experimental data comparing conventional COC-based IVM techniques against the claimed methods employing hiPSC-derived granulosa cells. Applicant argues that the data demonstrates surprising and marked improvements of the hiPSCs cells in many aspects of ex vivo oocyte maturation (Remarks pg. 12 para. 2). Applicant notes that the office acknowledged that the claimed hiPSC-derived granulosa cells outperformed endogenous-sourced granulosa cells at every critical step of the IVF process and that the improvements are commensurate in scope with the present claims (Remarks pg. 12 para. 3-4). Applicant argues that since Tilly is not the closest prior and does not address the same technical problem and has severe scientific inaccuracies the data present does not need to be compared to Tilly, but rather to Combelles, Obata and Fadini which are the closest prior art (Remarks pg. 12 para. 3-5). However, the argument that Tilly is not the closest prior art was not found to be persuasive, as explained above, since Tilly is also directed to a method of maturing oocytes for use in an assisted reproduction technology (0021) and would also be considered the closest prior art. It is maintained that Tilly teaches maturing immature oocytes using “synthetic” granulosa cells which include iPSC-derived granulosa cells (abstract, 0095-0096 and 0099). Tilley teaches that the “synthetic” granulosa cells are derived from multi-potent cells which include iPSC-derived granulosa cells in addition to embryonic stem cells, pluripotent stem cells, and very small embryonic-like cells (0005 and 0069). Therefore, the data presented from Piechota and Paulsen in the reply from Feb. 2, 2026 were not found to persuasive, since the results do not compare the iPSC-derived granulosa cells with the “synthetic” granulosa cells of the primary reference, Tilley. Although the results presented clearly show differences between granulosa cells derived from hiPSCs and endogenous support cells of the COC, the prior art reference, Tilly teaches maturing immature oocytes using “synthetic” granulosa cells which include iPSC-derived granulosa cells (abstract, 0095-0096 and 0099). Tilley teaches that the “synthetic” granulosa cells are derived from multi-potent cells which include iPSC-derived granulosa cells in addition to embryonic stem cells, pluripotent stem cells, and very small embryonic-like cells (0005 and 0069). No clear evidence was presented showing that the prior art would not produce similar results. In submitting evidence asserted to establish unobvious results, there is a burden on an applicant to indicate how the examples asserted to represent the claimed invention are considered to relate to the examples intended to represent the prior art and, particularly, to indicate how those latter examples do represent the closest prior art. See In re Borkowski, 595 F.2d 713, 184 USPQ 29 (CCPA 1974); In re Goodman, 339 F.2d 228, 144 USPQ 30 (CCPA 1964).
Response to Evidentiary Declaration under 37 CFR §1.132
The declaration of Dr. Christian Kramme filed on Apr. 14, 2026 under 37 CFR §1.132 has been considered but is ineffective to overcome the rejections of the claims under 35 U.S.C. §103.
Dr. Kramme states that the pending claims are directed to in vitro maturation which is the process of taking an already-formed, developmentally arrest oocytes in the germinal vesicle (GV) or metaphase (MI) stage and inducing the oocytes to resume meiosis and progress to the metaphase II (MII) stage. Dr. Kramme further explain this happens outside the body and requires precise coordination of a number of pathways under artificially conditions (Declaration para. 3). However, this argument was not found to be persuasive, since, as stated in the response to the arguments, Tilly teaches the ex vivo maturation of oocytes and the claimed method does not exclude the use of ovarian tissue. 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”. MPEP 2111.03
Dr. Kramme explains that the goal of IVM is to recreated the late-stage signaling environment that triggers and synchronizes meiotic resumption without compromising developmental competence (Declaration para. 4). Dr. Kramme further explains that follicle maturation which involves a multicellular, tissue-level process is different from oocyte maturation which involves a cell-intrinsic meiotic process and a follicle might mature while the oocyte fails to complete meiosis (Declaration para. 5). Dr. Kramme states that systems optimized for follicle maturation may not successfully effectuate oocyte maturation and could potential be neutral or detrimental to meiotic competence if the signals from the follicles are mistimed or misregulated (Declaration para. 6). However, these arguments were not found to be persuasive, since Tilly teaches clearly teaches a method of producing mature oocytes for a human subject for use in assisted reproduction technology (abstract, 0016, 0018, and 0021). Tilley teaches a method of maturing immature oocytes to produce a mature oocyte (abstract, 0016, and 0018) and teaches the co-culturing the immature oocytes with a population of “synthetic” granulosa cells generated from exogenous stem cells include human induced pluripotent stem cells (hiPSCs) (abstract, 0005, 0016, 0023, 0093-0094 and 0096). Additionally, Tilley teaches producing mature oocytes ex vivo for use in in vitro fertilization by co-culturing the “synthetic” granulosa cells with oocyte precursor cells and ovarian tissue which can have been previously frozen and stored (0032, 0099, 0100, and 109). It is maintained that one of the ordinary skill in the art would have been motivated to modify this teaching in Tilley to include co-culturing of immature oocytes for the benefit of producing mature oocytes. One of ordinary skill in the art would have had a reasonable expectation of success in making such a modification, since Tilley teaches that the “synthetic” granulosa cells for maturing oocytes ex vivo and the successful maturation of immature oocytes in vivo with the “synthetic” granulosa cells.
Dr. Kramme states that Tilly is directed to a different biological process than the claimed invention and is focused on the directed differentiation of multipotent cells into synthetic granulosa cells and the use of these cells in an artificial ovarian environment with the goal of supporting oocyte generation and follicle formation in a tissue based context (Declaration para. 7). Dr. Kramme argues that Tilly is directed to a method of in vitro gametogenesis (IVG) or artificial ovary systems where any oocyte maturation and follicle or follicle-like structures are developed in the context of ovarian tissue, extracellular matrix and 3D architecture and not to IVM where developmentally arrested cells are induced to resume meiosis (Declaration para. 8). Dr. Kramme explains that this distinction is important since early stage oocyte development relies on long-term somatic support for growth and follicular organization whereas IVM relies on short-term, precisely timed cues to regulate signaling and changes within an isolated oocyte (Declaration para. 9). These argument were not found to be persuasive, since in addition to teaching the production of synthetic granulosa cells for supporting oocyte generation and follicle formation in an artificial ovarian environment, Tilly teaches the ex vivo maturation of oocytes. The claimed method does not exclude the use of ovarian tissue. 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”. MPEP 2111.03 In addition, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., developmentally arrested cells and short-term support) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Dr. Kramme states that Tilly at para. 0096 describes in vivo cell behavior in a tissue-embedded context where the oocytes are subjected to endogenous architectural and paracrine signals which different from the ex vivo system of an isolated oocyte for IVM (Declaration para. 10). Dr. Kramme states that Tilly at para. 0099-1-0100 describes the ex vivo culture of ovarian tissue and these tissue based systems would not be extrapolated to isolated oocytes co-culture conditions which require many buffering and compensatory mechanisms (Declaration para. 11). However, these arguments were not found to be persuasive, since, as stated in the response to the arguments, Tilly teaches the ex vivo maturation of oocytes and the claimed method does not exclude the use of ovarian tissue. 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”. MPEP 2111.03
Dr. Kramme states that Tilly does not disclose that its synthetic granulosa cells adopt to a cumulus-like state and does not provide data demonstrating functional equivalence to endogenous cumulus cell in the context of meiotic control (Declaration para. 12). Additionally Dr. Kramme states that Tilly does not report and quantitative IVM endpoints to demonstrate that the synthetic granulosa cells could successfully induce meiotic maturation of isolated oocytes ex vivo (Declaration para. 13). However, these arguments were not found to be persuasive, since, as stated previously, Tilly teaches producing mature oocytes ex vivo for use in in vitro fertilization by co-culturing the “synthetic” granulosa cells with oocyte precursor cells and ovarian tissue which can have been previously frozen and stored (0032, 0099, 0100, and 109). Tilly further teaches the method where mature oocytes are produced by combining the synthetic granulosa cells, oocyte precursor cells and ovarian tissues (0027) and teaches that “any known methods and suitable conditions for making ex vivo artificial ovarian environments or for the maturation of immature follicles and oocytes to mature follicles and oocytes can be used” (0115). One of ordinary skill in the art would reasonably predict that at least at some point in time the ovarian tissue retrieved in Tilly would have to contain immature oocytes on the way to maturing the tissue. In addition, Tilly teaches contacting the immature oocytes in the in vivo ovarian tissue with the synthetic granulosa cells (0096). Accordingly, one of ordinary skill in the art would have had a reasonable expectation of success in using “synthetic” granulosa cells of Tilly for maturing immature oocytes ex vivo. Additionally, it is noted in Example 5 of Tilly, they show that granulosa cells differentiated from multi-potent cells produce ovarian steroidal hormones and conclude that these synthetic granulosa are useful for the ex vivo or in vivo formation of follicles, which assist in the production of mature follicles and oocytes. Furthermore, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., the granulosa cells adopt to a cumulus-like state and does not provide data demonstrating functional equivalence to endogenous cumulus cell in the context of meiotic control) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Dr. Kramme states that conventional IVM uses the subject’s own endogenous granulosa or cumulus cells which support late-stage oocyte maturation and Tilly does not disclose or teach that their synthetic granulosa cells would outperform the endogenous cells (Declaration para. 14). However, this argument was not found to be persuasive, since Tilly makes obvious the claimed method of co-culturing immature oocytes with granulosa cells generated from hiPSCs. Therefore, the function of outperforming endogenous cell must be inherent to the synthetic granulosa cells of Tilly, since synthetic granulosa cells of Tilly are also granulosa cells generated from hiPSCs as claimed. Additionally, in response to applicant's argument that Tilly does not disclose or teach that their synthetic granulosa cells would outperform the endogenous cells, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Dr. Kramme argues that hindsight reconstruction was used since Tilly addresses a different developmental bottleneck stage, the providing of somatic support for oocyte precursor cells and follicles within an artificial ovarian niche and does not provide guidance for IVM of retrieved oocytes (Declaration para. 15). This argument was not found to be persuasive, since, as stated before, in addition to teaching the production of synthetic granulosa cells for supporting oocyte generation and follicle formation in an artificial ovarian environment, Tilly teaches the ex vivo maturation of oocytes. The claimed method does not exclude the use of ovarian tissue. 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”. MPEP 2111.03
Conclusion
No claims are allowed.
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/EMILY A CORDAS/Primary Examiner, Art Unit 1632
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