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 .
Response to Amendment
The amendment filed 10/08/2025, amending claim(s) 23, 26, 28, 29, 30, 31, 32 and cancelling claim(s) 24, 25, 27, 33, 34 is acknowledged. Claims 23, 26, and 28-32 are pending and under examination. Applicant’s amendments to the claims have overcome each and every claim objection and 112(b) rejection previously set forth in the Non-Final Office Action mailed 4/08/2025.
The rejection of claims 23 and 28-32 under 35 U.S.C. 102(a)(1) as being anticipated by Cornell with support from Hong is withdrawn. Applicant added the new limitation of “wherein the ntECs are human umbilical vein endothelial cells (HUVECs) and wherein the ntECs comprise a recombinant nucleic acid molecule that comprises a nucleotide sequence that encodes BMP4 and a recombinant nucleic acid molecule that comprises a nucleotide sequence that encodes E40RF1”, which is not disclosed by Cornell.
Priority
The claims of the instant case are entitled to the priority date of provisional application 62/853,452, filed 05/28/2019.
Claim Interpretation
Claim 23 recites the term “engineered”. In view of [0050] of the specification, the term “engineered” is interpreted to further limit the cell population to be an artificially altered/manipulated cell population that expresses a recited nucleic acid molecule or polypeptide. In combination with the fact that E4ORF1 is not naturally present/expressed in endothelial cells, the claimed cell population is interpreted to be markedly different from a natural product.
Additionally, claim 23 recites the term “non-thymic endothelial cells (ntECs)”. In view of [0057] and Table A of the specification, this term is interpreted to read on endothelial cells that are not located in/do not form the thymus.
Claim Rejections - 35 USC § 103 – New, necessitated by 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.
Claim(s) 23, 26, and 28-32 is/are rejected under 35 U.S.C. 103 as being unpatentable over Cornell further in view of MSKCC (US20170292111 A1, published 10/12/2017) (US Patent Application Publication #9 of IDS).
Regarding claims 23 and 28-32, Cornell teaches an engineered E4ORF1+ non-thymic endothelial cell population (ntECs) ([0054], claims 86 and 98). Specifically, Cornell discloses the cell population comprising a recombinant nucleic acid sequence that comprises an E4ORF1 coding sequence under the control of an inducible promoter (claim 94) (i.e., operably linked to- claim 28), with the recombinant nucleic acid sequence being comprised within a lentiviral vector (claim 87) (claims 29-31) or a retrovirus [0034] (claim 32).
Cornell does not teach the ntEC population comprising a recombinant nucleic acid molecule that comprises a nucleotide sequence that encodes BMP4.
MSKCC teaches a population of thymic endothelial cells comprising recombinant BMP4 and E4ORF1 (claims 1, 2, and 6).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current invention to add the recombinant BMP4 nucleic acid molecule of MSKCC to the ntEC population taught by Cornell comprising a vector comprising E4ORF1 operatively linked to a promoter to arrive at the same invention. One would have a reasonable degree of success because MSKCC teaches expressing both BMP4 and E4ORF1 in an endothelial cell. Additionally, it is routine in the molecular biology art to express multiple genes of interest within a cell population, and to have the gene of interest be under the control of a heterologous promoter. An artisan would be motivated to make this combination because as taught by MSKCC, increasing expression of BMP4 can promote thymic regeneration (claim 1).
Response to Arguments
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, the Applicant specifically argues that because MSKCC also taught that endothelial cells derived from other organs were ineffective in promoting thymic regeneration, MSKCC teaches away. However, the other organs reference by the Applicant were cardiac or kidney endothelial cells, not endothelial cells derived from human umbilical vein.
Additionally, the Applicant cites Wertheimer (and several other references- see page 10 of Remarks) as support for MSKCC teaching away, as Wertheimer also taught that no effect on thymus regeneration was observed when endothelial derived from other tissues other than the thymus were used. However, Wertheimer also only compared thymus endothelial cells to cardiac and kidney endothelial cells. HUVECs are never mentioned in Ding et al. 2010 or Ding et al. 2011. Additionally, the only mention of HUVECs in Nolan et al. 2013 is briefly on pg. 209, col 2, where HUVECs overexpressing SFPI1 were used to test whether SFPI1 could bind to promoter regions CD37, MMP9, and TNF-alpha. HUVECs were not compared to any of the other endothelial cell types discussed in Nolan.
The Applicant has failed to distinctly point out why the teachings of MSKCC and Wertheimer related to cardiac and kidney endothelial cells are applicable to HUVECs (i.e., why would one assume HUVECs share the same properties with cardiac and kidney endothelial cells? Why would BMP4+ increase thymic regeneration as taught by MSKCC in thymic endothelial cells but not HUVECs?). For example, Kiyono (Kiyono, M., and M. Shibuya. "Inhibitory Smad transcription factors protect arterial endothelial cells from apoptosis induced by BMP4." Oncogene 25.54 (2006): 7131-7137.) teaches that HUVECs and human cardiac endothelial cells, such as human aortic and human coronary artery endothelial cells, had different responses when exposed to BMP4:
“BMP4 dose-dependently and selectively induced apoptosis of HUVEC and human dermal microvascular EC (HMVEC) (Figure 1a). Interestingly, however, it did not induce apoptosis of mature arterial EC such as human aortic EC (HAEC) and human coronary artery EC (HCAEC). These EC are highly resistant to BMP4 even at a concentration of 100ng/ml. Unlike BMP4, BMP7 had no apoptosis-inducing effect on EC under the same conditions (Figure 1b). We confirmed that this BMP7 induces phosphorylation of Smad1 in dose- and time-dependent manners (data not shown). On treatment with BMP4, a marked apoptosis of HUVEC and HMVEC, but not HAEC or HCAEC, was induced in a time dependent manner (Figure 1c and d).” (pg. 7132, col 1, para 1).
Therefore, the argument that MSKCC teaches away and that there is no motivation to combine the cited references is not persuasive.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In response to applicant's argument that “the present invention is based, in part, upon the surprising discovery that thymic regeneration can be induced in vivo by administering to a living subject non-thymic endothelial cells ("ntECs"), and specifically human umbilical vein endothelial cells (HUVECs) engineered to express recombinant adenovirus E40RF1 polypeptide and recombinant BMP4”, and “given this well-known tissue-specificity of endothelial cells, the finding of the present invention that exogenously expressed BMP4 was sufficient to enable E40RF1 expressing HUVECs to behave like thymic endothelial cells in the context of thymic organ regeneration, was unexpected”, 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). The Applicant fails to distinctly point out why a person skilled in the art being aware that clusters of numerous different transcription factors, angiocrine growth factors, adhesion molecules, and chemokines are expressed in unique combinations by endothelial cells of different organs - as demonstrated in Nolan et al. 2013 (which does not evaluate HUVECs) means that the current invention would not be obvious in view of the art.
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.
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/ALLISON MARIE JOHNSON/ Examiner, Art Unit 1638
/KEVIN K HILL/ Primary Examiner, Art Unit 1638