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 .
DETAILED ACTION
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.
Response to Amendments
Applicant’s amendments, Declaration submitted under 37 C.F.R. §1.132 by Christian Kramme, Ph.D., IDS, and response filed Feb. 2, 2026 have been received and entered into the case.
Status of the Claims
Claims 21, 22, 35, 37, 39-41, 43, 55, 57, and 61-71 are currently pending.
Claims 21, 22, 35, 37, 39, 40 and 43 are amended.
Claims 1-20, 23-34, 36, 38, 42, 44-54, 56, and 58-60 are cancelled.
Claims 61-71 are new.
Claims 21, 22, 35, 37, 39-41, 43, 55, 57, and 61-71 have been considered on the merits.
Claim Objections
The previous claim objections are withdrawn due to amendment.
Claim Rejections - 35 USC § 112
The claim rejections under 35 USC § 112, (a) or first paragraph (pre-AIA ), are withdrawn due to amendment.
New claim rejections under 35 USC § 112, (b) or second paragraph (pre-AIA ) have been added to address the claim amendments.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 21, 22, 35, 37, 39-41, 43, 55, 57, and 61-71 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.
Claim 21 is considered indefinite and its dependents, because in the preamble the claim recites “a method of preparing one or immature oocytes from a human subject for use in an assisted reproduction technology (ART) procedure”, however, the method steps conclude with the “maturing the one or more oocytes” and not with immature oocytes that are prepared for an ART technology. In other words, the preamble of the claim is directed to a method of preparing immature oocytes, however the steps of the claim appear to be directed towards maturing the immature oocytes into mature oocytes. It is unclear whether the immature oocytes are intended to be used for an ART procedure or the mature oocytes produced by the method are intended to be used for an ART procedure. For the sake of compact prosecution the phrase, will be interpreted to mean, “a method of maturing one or more immature oocytes from a human subject for use in an assisted reproduction technology (ART) procedure”.
All other claims depend directly or indirectly from rejected claims and are, therefore, also rejected under USC 112 for the reasons set forth above.
Appropriate correction is required.
Claim Rejections - 35 USC § 102
The claim rejections under 35 USC § 102 are withdrawn due to amendment.
Claim Rejections - 35 USC § 103
The claim rejections under 35 USC § 103 are withdrawn due to amendment. New claim rejections under 35 USC § 103 have been added to address the claim amendments.
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, 37, and 39-41 are rejected under 35 U.S.C. 103 as being unpatentable over Tilley et al. (US 2016/0237402 A1) (ref. of record).
With respect to claims 21 and 22, Tilley teaches a method of maturing immature oocytes to produce a mature oocyte (abstract, 0016, and 0018). As explained in the rejections under 35 USC § 112, Claim 21 is being interpreted as “a method of maturing one or more immature oocytes from a human subject for use in an assisted reproduction technology (ART) procedure”. With respect to step (ii) of claim 21 and claim 22, Tilley 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). Tilley 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).
Tilley 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, 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). 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 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. Additionally, one of ordinary skill in the art would reasonably predict that at least at some point in time the ovarian tissue retrieved in Tilley would have to contain immature oocytes on the way to maturing the tissue. In support, Tilley teaches contacting the immature oocytes in the in vivo ovarian tissue with the synthetic granulosa cells (0096).
With respect to claims 21 and 22, Tilley 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, Tilley 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 37, Tilley teaches the granulosa cells secrete ovarian derived hormones including estradiol (0022-0024).
Tilley 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 Tilley 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, Tilley 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, Tilley 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 Tilley (as applied to claims 21, 22, 37, and 39-41 above), and further in view of Combelles et al. (Human Reproduction, 2005) (ref. of record).
The teachings of Tilley can be found in the previous rejection above.
Tilley is silent with respect to the stage if the immature oocytes and does not teach the method where the one or more immature oocytes are germinal vesicle (GV)-stage oocytes or 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 Tilley so that the immature oocytes are germinal vesicle (GV)-stage or 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 Tilley so that the immature oocytes are germinal vesicle (GV)-stage or metaphase (MI)-stage oocytes, since these were known stages of immature oocytes which are 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 Tilley to include these stages of 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 Tilley (as applied to claims 21, 22, 37, and 39-41 above), and further in view of Obata et al. (US 2018/0251729 A1) (ref. of record).
The teachings of Tilley can be found in the previous rejection above.
Tilley 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 Tilley 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 Tilley 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 Tilley, 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 Tilley (as applied to claims 21, 22, 37, and 39-41 above), and further in view of Fadini et al. (Reproductive Biomedicine Online, 2009) (ref. of record).
The teachings of Tilley can be found in the previous rejection above.
Tilley 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, Tilley 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. Tilley 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. Tilley 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. Tilley 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 Tilley 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 Tilley 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 Tilley in further view of Fadini (as applied to claims 21, 22, 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 Tilley and Fadini can be found in the previous rejection above.
Neither Tilley 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 Tilley 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 Tilley 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 Tilley 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 Tilley in further view of Fadini (as applied to claims 21, 22, 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 Tilley and Fadini can be found in the previous rejection above.
Neither Tilley 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 Tilley 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 Tilley 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 Feb. 2, 2026 have been fully considered but they are not persuasive.
With respect to the rejections under 35 U.S.C. §102, Applicant argues that Tilley does not teach the specific combination of features recited in amended claims 21 and 22 (Remarks pg. 7 para. 3). Applicant argues that Tilley does not teach the retrieval of an immature (e.g. germinal vesicle (GV)-stage or metaphase (MI) stage oocyte) from a subject and instead teaches processes for the differentiation of the cells within follicular structures or ovarian tissue but not retrieved, immature oocytes ex vivo (Remarks pg. 7 para. 4).
Applicant argues that the methods disclosed in Tilley are performed on oocyte precursor cells within ovarian tissue and Tilley does not teach retrieving an immature oocyte that is pass the oocyte-precursor stage (Remarks pg. 7 last para. to pg. 8 para. 2). Applicant argues that Tilley is drawn to oocyte precursor and does not teach the suitability of immature-oocyte-stage cells for the ex vivo co culture (Remarks pg. 8 para. 3-4). Applicant argues that Tilley does not teach the claim step of co-culturing with either exogenous or hiPSC-generated granulosa cells with retrieved immature oocytes (Remarks pg. 8 para. 5). Applicant argues that Tilley does not the specific combination and arrangement of the claim’s features and does not teach the recited sequence and it would require modifying Tilley using unrelated embodiments to resemble the claim (Remarks pg. 8-9 bridging para.). The Applicant’s amendments limiting the claims to include retrieving immature oocytes, where the exogenous stem cells used to generate the granulosa cells are human induced pluripotent stem cells, and where the co-culturing of the immature oocytes and granulosa cells results in the maturing of the immature oocytes necessitated the withdrawal of the rejection. Applicant’s arguments are drawn to Tilley failing to teach this new limitation. However, this new limitation is addressed in the new rejection.
With respect to the rejections under 35 U.S.C. §103, Applicant argues that none of the cited references teach or suggest the use of granulosa cells that are generated from an exogenous iPSC source to mature an immature oocyte retrieved from a human subject (Remarks pg. 9 last para.). Specifically, Applicant argues that Tilley does not teach the ex vivo maturation an immature oocyte and Combelles, Obata and Fadini describe ex vivo maturation methods but utilize the granulosa cells present within the subject’s own cumulus-oocyte complexes (COCs) (Remarks pg. 10 para. 1-2). However, this argument was not found to be persuasive, since Tilley makes obvious the claim invention. Tilley clearly 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) as explained in the new rejections. Although, Tilley does not explicitly teach the co-culturing of immature 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. Additionally, one of ordinary skill in the art would reasonably predict that at least at some point in time the ovarian tissue retrieved in Tilley would have to contain immature oocytes on the way to maturing the tissue. In support, Tilley teaches contacting the immature oocytes in the in vivo ovarian tissue with the synthetic granulosa cells (0096).
Applicant argues that the exogenous stem cell-sourced granulosa cells of the instant claims are structurally distinct from the endogenously-sourced granulosa cells of the cited art, since they found that culturing with exogenous stem cell-sourced granulosa cells improve oocyte maturation efficiency compared to endogenously-sourced granulosa cells (Remarks pg. 10 para. 3). However, this argument was not found to be persuasive, since Tilley 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) and 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).
Applicant argues that the Declaration submitted under 37 C.F.R. § 1.132 by Dr. Christian Kramme provides evidence of the unexpected nature of the improved ex vivo oocyte maturation efficiency achieved by the exogenous, hiPSC-sourced granulosa cells compared to the COC-derived granulosa cels of the prior-art in vitro maturation (IVM) methods as shown in the para. 8 of the Declaration and the figure presented on pg. 11 of the Remarks (Remarks pg. 10 last para to pg. 11 para. 2). Applicant further argues that Dr. Kramme discusses and presents data demonstrating that the exogenous iPSC stem cell-sourced granulosa cells (Fertilo cells) outperformed endogenous-sourced granulosa cells at every critical step of the IVF process, from oocyte maturation to the formation of an euploid blastocytes and as shown in figure on pg. 12 (Remarks pg. 11-12 bridging para.). In addition, Applicant argues that the results are not limited by the method used to produce the hiPSC-derived granulosa cells as explained in the Declaration at para. 16-21 and therefore, the claims are commensurate in scope with the unexpected results (Remarks pg. 12 para. 2). Applicant argues that Dr. Kramme explains that the one possible reason for the improved outcome of using hiPSC-derived granulosa cells is that the cells have a younger phenotype that the patient’s own endogenous granulosa cells and secrete the maturation factor at a higher level (Remarks pg. 12-13 bridging para.). However, these arguments were not found to be persuasive for the same reason presented above, that Tilley makes obvious the claim invention. Tilley clearly 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) as explained in the new rejections.
Response to Evidentiary Declaration under 37 CFR §1.132
The declaration of Christian Kramme, PhD filed on Feb. 2, 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 previously published IVM (in vitro maturation) techniques often use the subject’s one endogenous support cells in the cumulus-oocyte complex (COC) which is typically retrieved with the subject’s oocytes and that the claimed invention is novel in that the granulosa or support cells are being generated from a hiPSC. Dr. Kramme further states that the use of these hi-PSC-derived granulosa cells markedly improves the rate of maturation of immature oocytes and the ability of the mature oocytes to undergo each of the key steps of an IVF procedure (Declaration para. 6).
Dr. Kramme states that the publication, Piechota (which Dr. Kramme is co-author), provides data demonstrating that immature oocytes had improved ex vivo oocyte maturation efficiency when co-cultured with exogenous, hiPSC-sourced granulosa cells compared to immature oocytes co-cultured with the COC-derived granulosa cells which are used in the prior art in vitro maturation (IVM) methods (Declaration para. 7-9). Dr. Kramme presents data from the reference showing that MII-stage oocytes prepared by the claimed method with hiPSC-sourced granulosa cells have gene expression signatures that closely align with in vivo mature oocytes while similar MII-stage oocytes prepared by the conventional method with COCs did not (Declaration para. 10-11). Dr. Kramme states the results showing increased mature oocyte morphology and gene expression demonstrates that the claimed method provides unexpected improvement over endogenous COC-based methods (Declaration para. 12).
In addition, Dr. Kramme states that the publication, Paulsen (which Dr. Kramme is co-author), provides further evidence of the improvements achieved by the hi-PSC-generated ovarian support cells (Declaration para. 13). Dr. Kramme presents data from Paulsen demonstrating that the exogenous iPSC stem cell-sourced granulosa cells (Fertilo cells) outperformed endogenous-sourced granulosa cells at every critical step of the IVF process, from oocyte maturation to the formation of an euploid blastocytes (Declaration para. 13). Dr. Kramme presents additional data from Paulsen showing that the exogenous iPSC stem cell-sourced granulosa cells also achieved significantly elevated implantation rates, clinical pregnancy rates and ongoing pregnancy rates (Declaration para. 14).
However, the data presented from Piechota and Paulsen 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).
Dr. Kramme further remarks that the patient populations used for the two different methods of ex vivo maturation of oocytes had the same pre-oocyte retrieval stimulation regimens (Declaration para. 15). Dr. Kramme further states that the results are not limited by a specific method used to produce the hiPSC-derived support cells and is reasonably applicable to the full class of hiPSC-derived support cells. Dr. Kramme further states that this supported by the data in Paulsen showing the ability of different batches of hiPSC-derived support cells produced using different manufacturing conditions to produce the same results (Declaration at para. 16-20 and 22). The data does appear to be commensurate in scope with the claims, however, for the reasons explained above it is not persuasive with respect to Tilley.
Dr. Kramme explains that the one possible reason for the improved outcome of using hiPSC-derived granulosa cells is that the cells have a younger phenotype that the patient’s own endogenous granulosa cells and secrete growth factors and steroids at a higher level (Declaration para. 21). However, this was not found to be persuasive, since Tilley also teaches that the “synthetic” granulosa cells increase ovarian-derived hormones and growth factors in the patient by secreting this factors (abstract, 0022 and 0138). Additionally, Tilly teaches a benefit of using the “synthetic” granulosa cells is that patients with no granulosa or theca cells can be treated (0068).
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EMILY ANN CORDAS whose telephone number is (571)272-2905. The examiner can normally be reached on M-F 9:00-5:30 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached on 571-272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/EMILY A CORDAS/Primary Examiner, Art Unit 1632