DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 12, 14, 16-20, and 23-24 are currently pending.
Claims 12, 14, and 16-20 are currently amended.
Claims 14 and 18-20 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 1-11, 13, 15, and 21-22 are cancelled.
Claims 12, 16-17, and 23-24 have been considered on the merits.
Note to Applicant
Claim 20 is both withdrawn and currently amended. It appears Applicant has accidentally amended claim 20 to include the status identifier “/Currently Amended” in the body of claim 20.
Withdrawn Rejections
The 35 U.S.C. 112(b) rejections made onto claims 12 and 14-22 are withdrawn in light of the amendments submitted on 12/19/2025.
New and Maintained Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 12 and 14-22 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 12 recites the limitation "target tissue" in lines 3-4. There is insufficient antecedent basis for this limitation in the claim. The claim states “wherein the isolated genetically engineered pluripotent cell does not differentiate into cerebrum and germ cells, and retains the ability to differentiate into tissues other than target tissues”. It is not clear if the claim is referring to “cerebrum and germ cells” as target tissues or if there are other tissues that the claimed cells are not capable of differentiating into. Appropriate clarification is required.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 12, 16-17, and 23-24 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al (Cell Stem Cell Resource, 2015) in view of Yamaji et al (Nature Genetics, 2008), all of which are references of record.
Regarding claim 12, Chen discloses isolated human embryonic stem cells (hESC) which contain a genetically engineered inducible knockout (iKO) of the Otx2 gene (pg. 242, col 2, para 2; pg. 238, col 2, para 2 spanning pg. 239). Chen discloses that in animal studies OTX2 is required during forebrain and midbrain development and that when the iKO of OTX2 is induced at the pluripotent stage, the cells resulted in a severe reduction in the expression of neuroepithelial markers and that the results suggest that OTX2 is required for inducing anterior neuroectoderm and/or conferring forebrain character to hPSC-derived neuroectoderm progenitors at an early stage; therefore meeting the claimed limitation of “wherein the isolated pluripotent cell does not differentiate into cerebrum and germ cells” (pg. 238, col 2, para 2 spanning pg. 239).
Chen does not teach that the otx2 gene knockout pluripotent cell also contains a simultaneous Prdm 14 gene knockout as required by claim 12.
However, Yamaji teaches a pluripotent stem cell to be an embryonic stem (ES) cell as required by claim 12 (pg. 1021, col. 2, para 5). The ES cell is genetically engineered to not differentiate into a predetermined type of cell through the disruption of a gene essential for a germ cell, specifically, the germ cell contains a double knockout of Prdm14 which Yamaji establishes that Prdm14 is the gene with the earliest-specific expression so far identified in the developing germ cell lineage (i.e. a gene essential for germ cell is disrupted) by claims 12 and 15 (pg. 1017, col. 2, para 1). Further, Yamaji teaches that the pluripotent cells are both male and female as required by claims 16-17 (pg. 1017, col. 2, para 1).
Claim 12 recites that the pluripotent cell “retains the ability to differentiate into tissues other then target tissues”, claim 23 recites “wherein the isolated genetically engineered pluripotent cell can differentiate into pancreatic cells”, and claim 24 recites “wherein the isolated genetically engineered pluripotent cell can differentiate into functional pancreatic cells”. These limitations appear to be inherent to the claimed cell. Further, the combination of Chen and Yamaji, which results in the claimed cell, would naturally contain the ability to differentiate into tissues other than the cerebrum and germ cells, based on the combination of the knockout of OTX2 and Prdm14 which are explicitly disclosed in the art. The MPEP states "[I]n order to rely on inherency to establish the existence of a claim limitation in the prior art in an obviousness analysis – the limitation at issue necessarily must be present, or the natural result of the combination of elements explicitly disclosed by the prior art” (MPEP, 2112 IV).
One of ordinary skill would find it obvious at the effective filling date of the instant invention to combine the Otx2 double inducible knockout taught by Chen with the Prdm14 double knockout taught Yamaji with the to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Yamaji teaches that that Prdm14 is the gene with the earliest-specific expression so far identified in the developing germ cell lineage (pg. 1017, col. 2, para 1) and Chen discloses that in animal studies OTX2 is required during forebrain and midbrain development and that when the iKO of OTX2 is induced at the pluripotent stage, the cells resulted in a severe reduction in the expression of neuroepithelial markers and that the results suggest that OTX2 is required for inducing anterior neuroectoderm and/or conferring forebrain character to hPSC-derived neuroectoderm progenitors at an early stage; therefore meeting the claimed limitation of “wherein the isolated pluripotent cell does not differentiate into cerebrum and germ cells” (pg. 238, col 2, para 2 spanning pg. 239). Therefore, both Prdm14 and Otx2 have effects on developing germ cells and the combination of Yamaji and Chen would be obvious to provide information on the complex germ cell relationship of Prdm14 and Otx2. One of ordinary skill in the art would have a reasonable expectation of success when combining Yamaji and Chen because both teach the necessary steps in order to perform a double knockout of Prdm14 and Otx2, respectively, in their entirety.
The combination of prior art cited above in all rejections under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. ___, 82 USPQ2d 1385 (2007)): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
In the present situation, rationales A, E, and F are applicable. The claims merely require the combining of known prior art methods as taught by Chen et al and Yamaji et al. to result in a pluripotent cell which contains both a Otx2 and Prdm14 knockout. The combination of Chen and Yamaji would lead to a predictable result absent results to the contrary. Both Chen and Yamaji teach that the respective gene knockouts render the cells unable to differentiate into either germ or neural/brain cell pathways, therefore the combination of the cell knockouts of Chen and Yamaji would predictably result in a cell which is unable to differentiate into a germ or neural/brain cell pathway. Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
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 12/19/2025 have been fully considered but they are not persuasive.
Applicant argues (Remarks, pg. 7 last para spanning pg. 8 para 2) that there is no motivation to combine, no expectation of success, and the combination employs hindsight reasoning in combining Chen and Yamaji.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, one of ordinary skill in the art would be motivated to make this combination because Yamaji teaches that that Prdm14 is the gene with the earliest-specific expression so far identified in the developing germ cell lineage (pg. 1017, col. 2, para 1) and Chen discloses that in animal studies OTX2 is required during forebrain and midbrain development and that when the iKO of OTX2 is induced at the pluripotent stage, the cells resulted in a severe reduction in the expression of neuroepithelial markers and that the results suggest that OTX2 is required for inducing anterior neuroectoderm and/or conferring forebrain character to hPSC-derived neuroectoderm progenitors at an early stage; therefore meeting the claimed limitation of “wherein the isolated pluripotent cell does not differentiate into cerebrum and germ cells” (pg. 238, col 2, para 2 spanning pg. 239). Therefore, both Prdm14 and Otx2 have effects on developing germ cells and the combination of Yamaji and Chen would be obvious to provide information on the complex germ cell relationship of Prdm14 and Otx2. In the alternative, a KSR analysis of the claims is also provided above and reproduced here. In the present situation, rationales A, E, and F are applicable. The claims merely require the combining of known prior art methods as taught by Chen et al and Yamaji et al. to result in a pluripotent cell which contains both a Otx2 and Prdm14 knockout. The combination of Chen and Yamaji would lead to a predictable result absent results to the contrary. Both Chen and Yamaji teach that the respective gene knockouts render the cells unable to differentiate into either germ or neural/brain cell pathways, therefore the combination of the cell knockouts of Chen and Yamaji would predictably result in a cell which is unable to differentiate into a germ or neural/brain cell pathway. Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
In response to applicant’s argument that there is also no reasonable expectation of success in combining Chen and Yamaji, one of ordinary skill in the art would have a reasonable expectation of success when combining Yamaji and Chen because both teach the necessary steps in order to perform a double knockout of Prdm14 and Otx2, respectively, in their entirety.
Applicant argues (Remarks, pg. 8) that a reference Zhang teaches that typically Otx2 acts as a barrier to primordial germ cell (PGC) markers and that when knocked out, these PGC markers are increased. Applicant states that because Prdm14 knockout acts to eliminate germline induction that Otx2 and Prdm14 have opposing effects resulting in an “overall outcome uncertain and unpredictable to a skilled artisan”.
In response, the claimed invention is directed to a cell containing two gene knockouts and the art teaches a method on how to achieve each gene knockout. Therefore it is unclear what outcome might be “uncertain and unpredictable” of the cell. Knockouts of multiple genes are well known in the art and based on the detailed methods of performing a gene knockout provided by Yamaji and Chen, one of ordinary skill would have a reasonable expectation of success in knocking out both Prdm14 and Otx2. Therefore, the arguments are not found persuasive.
Applicant argues (Remarks, pg. 9) that the claimed invention provides the unexpected result of being able to differentiate into tissues other than cerebrum and germ cells, recited in claim 12. Additionally, claims 23 and 24 which “recite the ability to differentiate into pancreatic cells” constitutes a specific utility and the retention of differentiation potential for the target tissue of the pancreas are not disclosed in the cited references.
In response, the argument is not found persuasive. Claim 12 recites that the pluripotent cell “retains the ability to differentiate into tissues other then target tissues”, claim 23 recites “wherein the isolated genetically engineered pluripotent cell can differentiate into pancreatic cells”, and claim 24 recites “wherein the isolated genetically engineered pluripotent cell can differentiate into functional pancreatic cells”. These limitations appear to be inherent to the claimed cell. Further, the combination of Chen and Yamaji, which results in the claimed cell, would naturally contain the ability to differentiate into tissues other than the cerebrum and germ cells, based on the combination of the knockout of OTX2 and Prdm14 which are explicitly disclosed in the art. The MPEP states "[I]n order to rely on inherency to establish the existence of a claim limitation in the prior art in an obviousness analysis – the limitation at issue necessarily must be present, or the natural result of the combination of elements explicitly disclosed by the prior art” (MPEP, 2112 IV).
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONSTANTINA E STAVROU whose telephone number is (571)272-9899. The examiner can normally be reached M-F 8:00-5:00.
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CONSTANTINA E. STAVROU
Examiner
Art Unit 1632
/ANOOP K SINGH/Primary Examiner, Art Unit 1632
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