Prosecution Insights
Last updated: April 19, 2026
Application No. 18/382,048

SERUM-FREE IN VITRO DIRECTED DIFFERENTIATION PROTOCOL FOR GENERATING STEM CELL-DERIVED BETA CELLS AND USES THEREOF

Non-Final OA §102§103§112
Filed
Oct 19, 2023
Examiner
MONTANARI, DAVID A
Art Unit
1632
Tech Center
1600 — Biotechnology & Organic Chemistry
Assignee
President and Fellows of Harvard College
OA Round
1 (Non-Final)
65%
Grant Probability
Favorable
1-2
OA Rounds
3y 10m
To Grant
99%
With Interview

Examiner Intelligence

Grants 65% — above average
65%
Career Allow Rate
491 granted / 754 resolved
+5.1% vs TC avg
Strong +49% interview lift
Without
With
+49.1%
Interview Lift
resolved cases with interview
Typical timeline
3y 10m
Avg Prosecution
42 currently pending
Career history
796
Total Applications
across all art units

Statute-Specific Performance

§101
4.7%
-35.3% vs TC avg
§103
33.1%
-6.9% vs TC avg
§102
15.9%
-24.1% vs TC avg
§112
31.7%
-8.3% vs TC avg
Black line = Tech Center average estimate • Based on career data from 754 resolved cases

Office Action

§102 §103 §112
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 . The instant application is a CON of 16/573,985 (abandoned), which is a CON of 14/975,158, now US Pat. No. 10,443,042. Claims 32-56 are examined in the instant application. 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. Claim 48 is 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 48 contains the trademark/trade name “Glutamax”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe Glutamax and, accordingly, the identification/description is indefinite. Claim Rejections - 35 USC § 102 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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action: A person shall be entitled to a patent unless – (a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention. Claim(s) 32, 33, 35, 36, 38, 40-43 and 46-56 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Rezania A. (US 2014/0186953 A1, published 7/3/2014). Regarding claims 32, 35 and 36, Rezania teaches an in vitro composition comprising a population of cells in serum-free culture medium comprising PDX-1, NKX6.1 cells, wherein the culture medium is supplemented with a ROCK inhibitor, a TGF-β signaling pathway inhibitor and a thyroid hormone signaling pathway activator (claims 1-22 and 32-36, parags. 45, 60, 67 and 145). Regarding claim 33, Rezania teach that their cells express insulin (parag. 158). Regarding claim 52, Rezania teaches that their cells expressed NGN3, NeuroD1, ISL1, ARX, PAX4 and PAX6 (parag. 45). Regarding claim 33, Rezania teach that their cells express insulin (parag. 158). Regarding claim 38, Rezania teaches that the ROCK inhibitor is Y-276632 (parag. 141). Regarding claims 40 and 41, Rezania teaches that the culture medium comprises T3 or GC-1 (parag. 67). Regarding claim 42, Rezania teaches that their culture medium further comprised ALK5 inhibitor II (parag. 101). Regarding claim 43, Rezania teaches that their culture medium can comprise zinc sulfate (claim 36). Regarding claims 46 and 47, Rezania teaches that their culture medium can comprise LDN193189 (claim 31). Regarding claim 48, Rezania teaches that their culture medium comprises Glutamax (parag. 150). Regarding claim 49, Rezania teaches that their culture medium comprises Vitamin C (parag. 90). Regarding claims 50 and 51, Rezania teaches that their culture medium comprises T3 and ALK5 inhibitor II (parags. 67 and 95). Regarding claims 53 and 55, Rezania teaches that their culture medium comprises heparin (claim 36). Regarding claims 54 and 56, Rezania teaches that their culture medium comprises insulin (parag. 152). Thus the teachings of Rezania clearly anticipate the invention of claims 32, 33, 35, 36, 38, 40-43 and 46-56. 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 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. Claim(s) 32 and 34 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rezania A. (US 2014/0186953 A1, published 7/3/2014) in view of Ravassard et al. 2011, JCI, Vol. 121(9) pgs. 3589-3597). Regarding claim 32, Rezania teaches an in vitro composition comprising a population of cells in serum-free culture medium comprising PDX-1, NKX6.1 cells, wherein the culture medium is supplemented with a ROCK inhibitor, a TGF-β signaling pathway inhibitor and a thyroid hormone signaling pathway activator (claims 1-22 and 32-36, parags. 45, 60, 67 and 145). Rezania does not teach: genetically modifying their cells. (i) Regarding genetic modification, Ravassard et al. teach the generation of a genetically modified cell line, EndoC-βH1, which exhibited a 3-fold increase of insulin (see Abstract and pg. 3591 col. 2 parag. 2 bridge pg. 3592 col. 1 parag. 1 and Fig. 6). Ravassard concludes by teaching “we have developed a robust innovative strategy for generating a stable and functional human pancreatic β cell line with glucose-inducible insulin secretion. Such a strategy could be exploited to produce other human cell lines, as long as a specific promoter is available. EndoC-βH1 cells could now be used to better understand human β cell physiology and in large-scale drug discovery in addition to as a preclinical model for developing cell replacement therapy in DM.” (pg. 3594 co. 2 parag. 1). Thus at the time of filing the ordinary artisan would have found it prima facie obvious to genetically modify the pancreatic endocrine cells of Rezania in view of the teachings of Ravassard to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to make such a modification since Ravassard teaches that genetically modifying pancreatic endocrine cells can improve their insulin secretion. There would have been a reasonable expectation of success that the pancreatic endocrine cells of Rezania could be genetically modified since Ravassard teaches that pancreatic endocrine cells can be routinely modified through the use of expression vectors. Thus, the cited art provides the requisite teachings and motivations to make and use the invention as claimed. Claim(s) 32, 37 and 45, is/are rejected under 35 U.S.C. 103 as being unpatentable over Rezania A. (US 2014/0186953 A1, published 7/3/2014) in view of Agulnick et al. (US 2010/0272695 Al). Regarding claim 32, Rezania teaches an in vitro composition comprising a population of cells in serum-free culture medium comprising PDX-1, NKX6.1 cells, wherein the culture medium is supplemented with a ROCK inhibitor, a TGF-β signaling pathway inhibitor and a thyroid hormone signaling pathway activator (claims 1-22 and 32-36, parags. 45, 60, 67 and 145). Rezania does not teach: (i) using a gamma secretase inhibitor. (i) Regarding claims 37 and 45 and the use of the gamma secretase inhibitor DAPT, Agulnick et al. teach a cell culture medium comprising DAPT and PDX1/NKX6.1 positive cells (parags. 174-175 and claim 10). Algunick continues to teach that by contacting cells with a gamma secretase inhibitor this provides for the cells to express PAX6 and insulin (pg. 187). Thus at the time of filing the ordinary artisan would have found it prima facie obvious to combine the teachings of Rezania regarding an in vitro composition comprising a population of cells in serum-free culture medium comprising PDX-1, NKX6.1 cells with the teachings of Algunick regarding using DAPT to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to make such a combination since Algunick teaches that contacting PDX1/NKX6.1 cells with a gamma secretase inhibitor facilitates their expression of pancreatic hormones like insulin and to express PAX6. There would have been a reasonable expectation of success that the DAPT of Algunick would work in the composition of Rezania since Rezania teaches using the same species of cells. Thus the cited art provides the requisite teachings and motivation to make and use the invention as claimed. Claim(s) 44 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rezania A. (US 2014/0186953 A1, published 7/3/2014) in view of Agulnick et al. (US 2010/0272695 Al) as applied to claims 34, 37 and 45 above, and further in view of Verfaillie et al. (US 2009/0092586 A1). The teachings of Rezania and Algunick are relied upon above in teaching a in vitro composition comprising a population of cells in serum-free culture medium comprising PDX-1, NKX6.1 cells and the gamma secretase inhibitor DAPT. Rezania and Algunick do not teach: the gamma secretase inhibitor XXI. Regarding the gamma secretase inhibitor XXI, Verfaillie et al. teach using compound E (aka XXI) with PDX1 positive cells (parag. 115). Thus at the time of filing the ordinary artisan would have found it prima facie obvious to modify the teachings of Rezania and Algunick regarding an in vitro composition comprising a population of cells in serum-free culture medium comprising PDX-1, NKX6.1 cells and gamma secretase inhibitor with the teachings of Verfaillie regarding using XXI to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to make such a modification since Verfaillie teaches that XXI is another species of gamma secretase inhibitor that can be used with PDX1 positive cells and one of ordinary skill in the art would it routine and obvious to use a another species of gamma secretase inhibitor since its functions the same as DAPT taught by Algunick. There would have been a reasonable expectation of success that the XXI of Verfaillie would work in the composition of Rezania and Algunick since Verfaillie teaches using another species of gamma secretase inhibitor. Thus the cited art provides the requisite teachings and motivation to make and use the invention as claimed. Claim(s) 32 and 39 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rezania A. (US 2014/0186953 A1, published 7/3/2014) in view of Xu et al. (2010, PNAS, Vol. 107(18), pgs. 8129-8134). Regarding claim 32, Rezania teaches an in vitro composition comprising a population of cells in serum-free culture medium comprising PDX-1, NKX6.1 cells, wherein the culture medium is supplemented with a ROCK inhibitor, a TGF-β signaling pathway inhibitor and a thyroid hormone signaling pathway activator (claims 1-22 and 32-36, parags. 45, 60, 67 and 145). Rezania does not teach: (i) using the ROCK inhibitor thiazovivin. (i) Regarding 39 and the use of the ROCK inhibitor thiazovivin, Xu et al. teach that the ROCK inhibitor thiazovivin significantly increases cell survival in contacted cells (pg. 8129 col. 2 parag. 1). Thus at the time of filing the ordinary artisan would have found it prima facie obvious to modify the teachings of Rezania regarding an in vitro composition comprising a population of cells in serum-free culture medium comprising PDX-1, NKX6.1 cells and a ROCK inhibitor with the teachings of Xu regarding the ROCK inhibitor thiazovivin arrive at the claimed invention. One of ordinary skill in the art would have been motivated to make such a modification since Xu teaches that thiazovivin is another species of ROCK inhibitor that can increase survival of cells and one of ordinary skill in the art would it routine and obvious to use another species of ROCK inhibitor since its functions the same as Y-276362 taught by Rezania. There would have been a reasonable expectation of success that the thiazovinin of Xu would work in the composition of Rezania since Xu teaches using another species of ROCK inhibitor. Thus the cited art provides the requisite teachings and motivation to make and use the invention as claimed. Conclusion No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID A MONTANARI whose telephone number is (571)272-3108. The examiner can normally be reached M-Tr 8-6. 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 at 571-272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /DAVID A MONTANARI/Examiner, Art Unit 1632
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Prosecution Timeline

Oct 19, 2023
Application Filed
Feb 07, 2026
Non-Final Rejection — §102, §103, §112 (current)

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Study what changed to get past this examiner. Based on 5 most recent grants.

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Prosecution Projections

1-2
Expected OA Rounds
65%
Grant Probability
99%
With Interview (+49.1%)
3y 10m
Median Time to Grant
Low
PTA Risk
Based on 754 resolved cases by this examiner. Grant probability derived from career allow rate.

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