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 .
Application Status
This action is written in response to applicant’s correspondence received 7/25/2025. Claims 1-9, 11-98, and 103 are cancelled. Claims 10, 99-102 and 104-147 are currently pending. Claims 134-147 are new.
The restriction requirement mailed December 6, 2022 is still deemed proper. The claims directed to non-elected inventions were cancelled in the amendment filed on March 6, 2023. Applicant's elected Group IV (claims 10-48) without traverse in the reply filed March 6, 2023.
Applicant amended claim 10 to limit the increased CD47 expression allowing survival of the hypoimmunogenic cell for at least 2 week following transplantation into a “without immunosuppression” and added new claims 134-147.
Nucleotide and/or Amino Acid Sequence Disclosures - Compliant
Applicant added sequence identifiers to nucleotide sequences appearing in the specification amendment filed 7/25/2025 to overcome the specific deficiency.
Claim Rejections - 35 USC § 112 – Written Description – new necessitated by amendment
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 10, 99-102, and 104-147 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This new rejection is necessitated by Applicant’s amendment filed 7/25/2025 to add claims 134-147.
The broadest reasonable interpretation of the claimed invention is a genus of isolated hypoimmunogenic cells comprising a) one or more genetic alterations that reduce expression of a functional endogenous Major Histocompatibility Antigen Class I (HLA-I) complex as compared to a parental cell; and one or more genetic alterations that reduce expression of a functional endogenous Major Histocompatibility Antigen Class II (HLA-II) complex as compared to the parental cell; b) one or more genetic alterations that increase expression of a functional CD47 protein as compared to the parental cell, wherein the increased CD47 expression is sufficient to allow for the hypoimmunogenic cell to survive for at least 2 weeks following transplantation into a subject without immunosuppression; and c) a safety switch; wherein the hypoimmunogenic cell is an islet cell.
The dependent claims further comprise adding or removing additional genes or a specific gene. To avoid a lengthy office action, these dependent claims are also rejected for the same reasons as set forth below.
The prior art and the specification do not disclose that the genus of hypoimmunogenic islet cells comprising (a), (b), and (c) are found in nature.
The instant disclosure contemplates a genus of hypoimmunogenic islet cells.
On page 24, the specification discloses that HIP cells can be differentiated into beta-like pancreatic cells or islet organoids ("dHIP beta cells"). The specification, on page 50, provides a working example of differentiating mouse HIP cells into islet cells using techniques adapted from Liu et al., Exp. Diabetes Res 2012:201295, incorporated by reference and in particular for the differentiation techniques outlined therein. The specification, on page 50, further discloses iPS cells that have been engineered to possess hypoimmunogenicity (e.g. by the knockout of B2M and CIITA and the knock in of CD47) and then are differentiated into a cell type for ultimate transplantation into subjects. The specification provides working examples of generating B2M-/- CIITA-/- Cd47tg mouse iPSCs and the transplantation of mouse HIP endothelial cell derivatives (miECs) into immunocompetent mice recipients with long-term survival (Example 4) and working examples of transplantation of human iPSC derived cardiomyocytes and endothelial cells into humanized mice (Examples 5-8). The specification discloses that, in some embodiments, the HIP cells are differentiated into beta-like cells or islet organoids for transplantation to address type I diabetes mellitus (T1DM) (pp. 40-41).
However, the specification does not provide a working example of the claimed hypoimmunogenic islet cells (or of dHIP beta cells) being transplanted into a subject and further having increased CD47 expression sufficient to allow the hypoimmunogenic islet cell to survive for at least 2-6 weeks following transplantation into a subject.
Page 48 indicates that the cells can be generated using episomal vectors, piggyBac transposon, synthetic mRNAs, microRNAs, recombinant proteins and small molecule drugs.
Pages 29-24 contemplate down regulation of a gene using interfering RNA or gene editing using CRISPR, TALEN, Zinc finger nuclease technologies.
The prior art teaches using a TALEN, a CRISPR nuclease, a lentiviral vector, an adenoviral vector, or a combination thereof in human pluripotent stem cells to reduce expression or knock out MHC-I and/or MHC-II genes (see Meissner WO2016183041A2; as cited in the IDS filed May 20, 2020). Prior art reference Zheng teaches introducing genetic alterations to cells using a ZFN, a TALEN, a CRISPR nuclease, and a lentiviral vector, or a combination thereof (see Zheng et al. Stem Cells, Vol 34, 9, pp. 2269-2275; 2016; of record).
The claimed invention has written description for CRISPR nuclease technology involving reduction or eliminating endogenous MHC I and II (HLA-I and II) and for expressing exogenous CD47 in isolated human cells.
In addition, neither the specification nor the prior art describe the claimed hypoimmunogenic islet cells comprising one or more knock downs using a TALEN or zinc finger nucleases. Each type of modification requires a different method and/or materials. While the specification generically contemplates these limitations, there is nothing in the disclosure that describes what compound, including gene editing products, small molecules, microRNAs, or recombinant proteins would result in the hypoimmunogenic islet cells having the desired reduction of endogenous HLA-I and HLA-II and increase of CD47 with a safety switch gene. A search of the prior art does not result in compounds (gene editing products, small molecules, microRNAs, or recombinant proteins) for making the genus of claimed hypoimmunogenic islet cells were well-known in the prior art. provide any reliable information about other means of achieving such an increase. The claimed invention as a whole is not adequately described if the claims require essential or critical elements that are not adequately described in the specification and that is not conventional in the art as of applicants effective filing date. Possession may be shown by actual reduction to practice. There is no actual reduction to practice, no disclosure of sufficiently detailed drawings or disclosure of sufficiently detailed relevant identifying characteristics in the specification of the compounds, including TALENS or zinc finger nucleases for making the genetically modified hypoimmunogenic islet cells. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. This is analogous to the instant claims because here the applicant only described genetic alterations via CRISPR-Cas complex (page 64). The specification provided only the bovine sequence. Thus, the skilled artisan cannot envision that the application had written support for the genus of hypoimmunogenic islet cells as recited in the claims.
In view of the foregoing, it is clear that the instant specification fails to convey that the inventors had possession of the genus of hypoimmunogenic islet cells as recited in the instant claims as of the effective filing date sought in the instant case.
Response to Arguments
Applicant's arguments filed 07/25/2025 have been fully considered but they are not persuasive. Applicant argues, on pages 2-3 of the remarks, the instant claims contemplating a genus of hypoimmunogenic islet cells are supported by written description by summarizing and quoting portions of the written description rejection in the Non-Final Office Action mailed 2/25/2025 (pages 7-8). Applicant argues that because TALENs or zinc finger nucleases are mentioned in the specification that they have sufficient written description support. Applicant argues that the test for sufficiency is whether the disclosure "reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date." Applicant further argues that the test for possession requires determining how a person of ordinary skill in the art would understand the four corners of the specification. Regents of the Univ. of California v. Broad Inst., Inc., 136 F.4th 1367, 1383 (Fed. Cir. 2025)(citations omitted) and states that it is well-established that working examples or an actual reduction to practice are not necessary to satisfy the written description requirement. Id. at 1383. Applicant argues that the specification provides: a working example of generating a hypoimmunogenic islet cell; hypoimmunogenic beta-like cells or islet organoids generated for transplantation; many molecular techniques that are well-known in the art for generating the hypoimmunogenic islet cells; and hypoimmunogenic cells differentiated from hypoimmunogenic pluripotent cells that survive transplantation for two weeks or longer. Applicant concludes that the inventors contemplated, and were in clear possession of, an isolated hypoimmunogenic islet cell having reduced HLA-I, reduced HLA-II, increased CD47 at a level that is sufficient to survive at least two weeks following transplantation, and a safety switch and further that the invention draws upon the specification's disclosure, actual examples, and techniques known in the art to provide the claimed hypoimmunogenic islet cells.
The Office disagrees. MPEP 2163 I states that “Compliance with the written description requirement is a question of fact which must be resolved on a case-by-case basis. Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116 (Fed. Cir. 1991)”. In the instant case, the Office disagrees with Applicant’s position because while the specification has written support for genetic alterations made by CRISPR for making the modified hypoimmunogenic islet cells, the specification does not have written support for the genetic alterations being made by zing finger nucleases or TALENs. Instant claim 132 indicates that the limitation reads on a large genus of products have the desired functional limitation (genetic alterations are introduced using a ZFN, TALEN, CRISPR nuclease, a viral vector or a combination thereof. There is not sufficient written description for the entire genus or subgenus of the instant claims and in particular “one or more genetic alterations that reduce expression of a functional endogenous HLA-I complex”, “one or more genetic alterations that reduce expression of a functional endogenous HLA-II complex”, and “one or more genetic alterations that increase the expression of a function CD47 protein”. The working examples for the claims only provide support for CRISPR/Cas9 induced genetic alterations. Neither the specification nor the prior art describe the claimed hypoimmunogenic islet cells comprising one or more knock downs using a TALEN or zinc finger nucleases. Each type of modification requires a different method and/or materials, yet there is nothing in the disclosure that describes what compound, including gene editing products, small molecules, microRNAs, or recombinant proteins would result in the hypoimmunogenic islet cells having the desired reduction of endogenous HLA-I and HLA-II and increase of CD47 with a safety switch gene. Neither the prior art nor the as-filed specification described viral vectors that can introduced a genetic alteration to a cell. Not only is there no actual reduction to practice, but there is also no disclosure of sufficiently detailed drawings or disclosure of sufficiently detailed relevant identifying characteristics in the specification of the TALENS or zinc finger nucleases for making the genetically modified hypoimmunogenic islet cells. Thus, the skilled artisan cannot envision that the application had written support for the genus of hypoimmunogenic islet cells as broadly recited in the claims. Adequate written description of agents based on the specification contemplating the agents is not found persuasive, even when the preparation of such agents is routine and conventional. See MPEP 2163, Amgen Inc. v. Sanofi. Therefore, the written description rejection under 112(a) is maintained.
Claim Rejections - 35 USC § 103 - withdrawn
Rejection under 35 U.S.C. 103 of claims 10, 99-100, 102, 104-122, 124, and 126-133 as being unpatentable over Meissner, in view of Zheng and Teraoka, of claim 101 as being unpatentable over Meissner, Zheng, and Teraoka, and further in view of Mohit, and of claims 123 and 125 as being unpatentable over Meissner, Zheng, and Teraoka, and further in view of Chen are withdrawn at least in view of Applicant’s amendment to include “without immunosuppression” to claim 10 and newly added claims 134-147.
Claim Rejections - 35 USC § 103 – new necessitated by amendment
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 10, 99-100, 102, 104-122, 124, and 126-147 are rejected under 35 U.S.C. 103 as being unpatentable over Meissner (Meissner et al.; WO2016183041A2; published November 17, 2016; as cited in the IDS filed May 20, 2020) in view of Zheng (Zheng et al., Stem Cells, Vol 34, 9, pp. 2269-2275; published June 27, 2016) and Teraoka (Teraoka et al. Expression of recipient CD47 on rat insulinoma cell xenografts prevents macrophage-mediated rejection through SIRPα inhibitory signaling in mice. PloS one, 8(3); published March 5, 2013). This new rejection is necessitated in view of Applicant’s amendment to include “without immunosuppression” to claim 10 and newly added claims 134-147 filed 7/25/2025.
Meissner’s disclosure is directed to universal donor stem cells that do not express one or more human leukocyte antigens (e.g., HLA-A, HLA-B and/or HLA-C) corresponding to MHC-I and MHC-II human leukocyte antigens, thereby rendering such cells hypoimmunogenic (see entire document). Meissner teaches universal donor stem cells useful for overcoming the immune rejection in cell-based transplantation therapies (see abstract).
Regarding claims 10, 104-106, 134, and 139-140, Meissner teaches using genome editing tools to create hypoimmunogenic cells with reduced expression of functional MHC I or MCH-II human leukocyte antigens compared to a parental cell (see p. 2, lines 14-21; claims 1-3). Meissner further teaches these immunogenic cells with knock in expression of CD47 (see Fig. 23 and p. 3, lines 9-26; p. 4, lines 8-32) and that overexpression of CD47 assists engraftment of stem cell-derived transplants by protecting cells from macrophage engulfment (see p. 16, lines 8-16; and Fig. 23). Meissner further teaches that the hypoimmunogenic cell may be differentiated into relevant cells types such as a pancreatic beta cell, which is an islet cell (see p. 5, lines 1-5; p. 40, lines 1-26; p. 85, line 27 to p. 86, line 2; and FIGS. 28A, 28H, and 28I). Meissner teaches that the disclosed universal donor stem cell-derived cell products will be immunoprivileged and will be protected from autoimmune rejection (see p. 40, lines 1-26). Meissner further teaches that injecting genome-edited cells having reduced HLA expression results in teratoma formation (see Table 1 and p. 79, line 31 to p. 80, line 14). Meissner teaches the improved engraftment of double knockout genome-edited stem cells in humanized mice over a period of at least 5 weeks post engraftment (see Fig. 29B; p. 10, lines 12-20; Fig. 6).
However, Meissner does not teach hypoimmunogenic cells comprising a safety switch, which is defined in the instant specification as a function in hypoimmunogenic pluripotent cells that comprise a "suicide gene" or "suicide switch" and that can cause the death of the hypoimmunogenic pluripotent cells should they grow and divide in an undesired manner and further does not specifically teach that the increased CD47 expression is sufficient to achieve long-term survival of at least 2 weeks.
Zheng’s disclosure is directed to improvements in human embryonic stem cells for regenerative medicine (see entire document). Zheng discloses recent approaches to generate universally compatible hESCs through the silencing or deletion of HLAs or genes essential for HLA expression, including β-2-microglobulin and class-II MHC transactivator, as well as the induction of immunosuppression via the ectopic expression of non-classical HLAs (e.g., HLA-E and -G), cytotoxic T lymphocyte antigen 4 fused with immunoglobulin, and programmed death ligand-1 (see abstract). Zheng further warns that teratomas can be formed by residual hPSCs left among differentiated cells, especially in an immunosuppressed host (p. 2273, right column, para 1).
Regarding claims 10, 104-106, 134, and 139-140, Zheng teaches that the genetic introduction of a “suicide” gene into hPSCs has been shown to be promising for eliminating teratomas or malignant tumors formed by residual hPSCs (see p. 2273; right column, paras 4-5). Zheng further teaches that the safety switch/suicide gene can be expressed constitutively or conditionally as appropriate (see p. 2273; right column, paras 4-5).
Teraoka’s disclosure is directed to improving methods of xenotransplantation by overexpression of CD47 in islet cells, whereby genetic induction of the expression of CD47 in the xenogeneic donor cells could provide inhibitory signals to the subject’s macrophages for preventing macrophage-mediated xenograft rejection (see entire document). Teraoka further teaches that interspecies incompatibility of CD47 is responsible for in vitro phagocytosis of xenogeneic cells by host macrophages (see abstract).
Regarding claims 10, 104-106, 134, and 139-140, Teraoka teaches that genetic manipulation of xenogeneic cells for host-type CD47 expression would be particularly useful to reduce phagocytosis by macrophages (see p. 7, right column, para 2; Fig. 3). Teraoka suggests that immune responses to genetic manipulations affecting CD47 expression should be studied in immunocompetent animal model enabling long-term observation (see p. 7, right column, para 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the instant application to have modified the hypoimmunogenic islet cells as taught by Meissner with the genetic introduction of the safety switch of Zheng to arrive at the claimed invention of transplanting hypoimmunogenic cells that survive in a subject for at least 2 weeks or longer based on the desired treatment plan as described in Teraoka. Meissner and Zheng both teach the importance of reducing HLA expression in donor cells to prevent immune rejection in cell-based transplantation therapies (see abstract and Fig. 1, respectively. Meissner teaches that injecting genome-edited cells having reduced HLA expression results in teratoma formation (see Table 1 and p. 79, line 31 to p. 80, line 14) and Zheng further warns against teratoma formation as a result of grafts (see p. 2273, right column, para 1). Meissner teaches the improved engraftment of double knockout genome-edited stem cells in humanized mice over a period of at least 5 weeks post engraftment even without additional CD47 expression (see Fig. 29B; p. 10, lines 12-20; Fig. 6). The ordinary artisan would have been motivated to improve Meissner’s hypoimmunogenic cells in order to prevent tumor formation as taught in Zheng (see p. 2273; right column, paras 4-5). The ordinary artisan would have been further motivated to optimize the expression of CD47 to prevent macrophage-mediated xenograft rejection and to do so in an immunocompetent animal model (without immunosuppression) as taught in Teraoka and to optimize the treatment for longer survival times beyond the at least 5 weeks after transplantation as taught in Meissner. It would have amounted to routine optimization. Furthermore, Both Meissner and Teraoka teach increasing expression of CD47 protects transplanted cells from engulfment by phagocytosis, thus increasing cell survival (see discussion above). Meissner teaches the improved engraftment of double knockout genome-edited stem cells in humanized mice over a period of at least 5 weeks post engraftment (see Fig. 29B; p. 10, lines 12-20; Fig. 6). The limitation “wherein the increased CD47 expression is sufficient to allow for the hypoimmunogenic cell to survive for at least 2 weeks following transplantation into a subject” is a functional limitation that would necessarily result from the prior art teachings of increased CD47 expression and lacks any additional structure beyond “one or more genetic alternations that increase expression of a functional CD47 protein as compared to the parental cell”. Although the teaching of Meissner and Zheng and Teraoka is silent with respect to the limitation (wherein the increased CD47 expression is sufficient to allow for the hypoimmunogenic cell to survive for at least 2(4,6) weeks following transplantation into a subject) in claims 10, 104-105, 134, 139-140 and the limitation (wherein the level of CD47 protein expressed by the hypoimmunogenic cell is at least about 3.5 fold greater than the level of CD47 protein expressed by the parental cell) in claim 106, Meissner and Zheng and Teraoka make obvious all of the claimed structural limitations, so the functional effects of the claimed product are considered to be embraced by the product made obvious by the art cited in the instant 103 rejection.
Where, as here, the claimed and prior art products are identical or substantially identical, or are produced by identical or substantially identical processes, the PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his claimed product. See In re Ludtke 441 F.2d 660, 169 USPQ 563 (CCPA 1971). Whether the rejection is based on "inherency" under 35 USC 102, or "prima facie obviousness" under 35 USC 103, jointly or alternatively, the burden of proof is the same, and its fairness is evidenced by the PTO's inability to manufacture products or to obtain and compare prior art products. In re Best, Bolton, and Shaw, 195 USPQ 430, 433 (CCPA 1977) citing In re Brown, 59 CCPA 1036, 459 F.2d 531, 173 USPQ 685 (1972).
Therefore, Meissner and Teraoka necessarily teach the functional limitation that “increased CD47 expression is sufficient to allow for the hypoimmunogenic cell to survive for at least 2 weeks following transplantation into a subject”. The ordinary artisan would have had a reasonable expectation of success because Meissner, Zheng, and Teraoka’s disclosures teach biosafety improvements on gene therapies and longer cell survival times after transplantation with CD47 overexpression. Thus, the claimed invention as a whole is prima facie obvious.
Regarding claims 99, 100, 102, 135-136, and 138, Zheng teaches that the safety switch comprises a suicide gene that is HSV-tk or an inducible Caspase protein (see p. 2273; right column, paras 4-5).
Regarding claims 107 and 141, Meissner teaches that the hypoimmunogenic cell is less susceptible than the parental cell to rejection when transplanted into a subject (see p, 2, lines 10-13; p. 3, lines 17-26; p. 27, lines 26-32 and p. 28, lines 1-7; claims 15, 28, 50, 62).
Regarding claims 108 and 142, Meissner teaches increasing expression of CD47 to prevent macrophage phagocytosis when transplanted into a subject (see p. 16, lines 8-16).
Regarding claims 109 and 143, Meissner teaches that the hypoimmunogenic cell is derived from a pluripotent cell (see p. 81, lines 16-25; p. 84, lines 11-19; and claims 1, 2, 18, and 30).
Regarding claims 110 and 144, Meissner teaches that the pluripotent cell is an induced pluripotent stem cell, an embryonic stem cell, or somatic stem cell (see p. 10, lines 26-30; p. 28, lines 24-32; p. 77, lines 23-27; Figs. 9A-9D; and Fig. 27).
Regarding claims 111-114 and 118, Meissner teaches genetic alteration, namely knock-outs, that reduce and knock out the expression of β-2 microglobulin (B2M) (see p. 41, lines 13-32 and p. 42, lines 1-19; p. 45, lines 3-9; p. 48, lines 3-32; p. 79, lines 8-23).
Regarding claims 115-117, Meissner teaches that the one or more genetic alterations that reduce or knockout expression of the one or more HLA-I genes comprise an HLA-A gene, an HLA-B gene, and an HLA-C gene (see abstract; p. 2, lines 14-21; p. 81, lines 5-15; claims 21-23, 48, 59, and 66-67; and Fig. 14G-14J and Fig. 16G).
Regarding claims 119-122, 124, and 126 Meissner teaches that the one or more genetic alterations that reduce or knockout expression of one or more HLA-II genes comprise an HLA-DR and/or the one or more HLA-II associated genes comprise a CIITA gene (see p. 81, lines 5-15; p. 84, lines 22-32; p. 86, lines 7-22; Fig. 28F; and claims 9, 21, 37, 39, 44, 47, 65, 74-76; 98, 100, 102, and 104).
Regarding claim 127, Meissner teaches that the one or more genetic alterations that reduce expression of the HLA-I B2M gene reduce surface expression of B2M (see p. 5, lines 18-23; p. 6, lines 1-5; p. 7, lines 16-32; Fig. 16C and 40C-G).
Regarding claim 128, Meissner teaches that the reduced expression of the HLA-II CIITA gene comprises reduced surface expression of CIITA (see p. 5, lines 12-17; p. 5, lines 24-32; p. 7, lines 22-32).
Regarding claims 129-131 and 145-147, Meissner teaches one or more genetic alterations that increase expression of CD47 protein comprising knock-in of human CD47 under CAG promoter (see Fig. 23, p. 16, lines 8-16; p. 62, lines 28-32 and p. 63, lines 1-13; and p. 84, lines 11-19).
Regarding claim 132, Meissner teaches using a TALEN, a CRISPR nuclease, a lentiviral vector, an adenoviral vector, or a combination thereof in human pluripotent stem cells to reduce expression or knock out MHC-I and/or MHC-II genes (see p. 2, lines 14-21; and Figs. 16A-16G, 21A-21D, and 22A-C). Zheng teaches introducing genetic alterations to cells using a ZFN, a TALEN, a CRISPR nuclease, and a lentiviral vector, or a combination thereof (see Table 1; p. 2272, left column, paras 2-3).
Regarding claim 133, Meissner teaches that the hypoimmunogenic cell is human (see abstract; p. 2, lines 14-21; and p. 40, lines 19-26).
Therefore the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claim 101 is rejected under 35 U.S.C. 103 as being unpatentable over Meissner (Meissner et al.; WO2016183041A2; published November 17, 2016; as cited in the IDS filed May 20, 2020) in view of Zheng (Zheng et al., Stem Cells, Vol 34, 9, pp. 2269-2275; published June 27, 2016) and Teraoka (Teraoka et al. Expression of recipient CD47 on rat insulinoma cell xenografts prevents macrophage-mediated rejection through SIRPα inhibitory signaling in mice. PloS one, 8(3); published March 5, 2013), as applied to claims 10, 99-100, 102, 104-122, 124, and 126-147 above, and further in view of Mohit (Mohit and Rafati, Molecular immunology, 56(4), 599-611; published December 31, 2013).
The teachings of Meissner, Zheng and Teraoka are discussed above. The teachings do not make obvious using an E. Coli deaminase gene (EC-CD) as the suicide gene.
Mohit’s disclosure is directed to strategies to potentiate efficacy and enhance specificity of biological deliver approaches for gene therapy (see title).
Regarding claim 101, Mohit teaches expressing the suicide gene E. coli cytosine deaminase for cancer gene therapy (see p.599, right column, paras 1-2). Mohit further teaches that the enhancement of the immune response against tumor cells is one of several approaches to improve cancer gene therapy (see p.599, right column, para 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to have modified the hypoimmunogenic cells as taught in Meissner, Zheng, and Teraoka by substituting the HSV-tk gene or inducible Caspase gene for the EC-CD suicide gene as taught by Mohit. The ordinary artisan could have tried the EC-CD suicide gene because it would be a simple substitution of one known suicide gene for another. The ordinary artisan would have had a reasonable expectation of success because Meissner, Zheng, Teraoka, and Mohit’s disclosures teach biosafety improvements on gene therapies by reducing HLA expression in human pluripotent stem cells. Thus, the claimed invention as a whole is prima facie obvious.
Claims 123 and 125 are rejected under 35 U.S.C. 103 as being unpatentable over Meissner (Meissner et al.; WO2016183041A2; published November 17, 2016; as cited in the IDS filed May 20, 2020) in view of Zheng (Zheng et al., Stem Cells, Vol 34, 9, pp. 2269-2275; published June 27, 2016) and Teraoka (Teraoka et al. Expression of recipient CD47 on rat insulinoma cell xenografts prevents macrophage-mediated rejection through SIRPα inhibitory signaling in mice. PloS one, 8(3); published March 5, 2013), as applied to claims 10, 99-100, 102, 104-122, 124, and 126-147 above, and further in view of Chen (Chen et al., Biol Res 48, 59. published October 27, 2015).
The teachings of Meissner, Zheng, and Teraoka are discussed above. However the teachings do not make obvious knocking out HLA-DP (claim 123) and HLA-DQ (claim 125) as the one or more HLA-II genes of the hypoimmunogenic cells.
Chen’s disclosure is directed to optimizing human embryonic stem cell allografting by reducing expression of HLA-II genes (see abstract).
Regarding claims 123 and 125, Chen teaches knocking out CIITA to disrupt the expression of HLA-II genes HLA-DP and HLA-DQ (see p. 2, right column, para 3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to have modified the hypoimmunogenic cells as taught in Meissner, Zheng, and Teraoka by instead reducing the expression of HLA-DP and HLA-DQ as taught by Chen. The ordinary artisan could have tried reducing HLA-DP and HLA-DQ, because it would be a simple substitution of one known HLA-II gene for another. The ordinary artisan would have had a reasonable expectation of success because Meissner, Zheng, Teraoka, and Chen’s disclosures teach biosafety improvements on gene therapies by reducing HLA expression in human pluripotent stem cells. Thus, the claimed invention as a whole is prima facie obvious.
Therefore the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Response to Arguments
Applicant's arguments filed 07/25/2025 have been fully considered but they are not persuasive. Applicant argues on page 5 that the amended claims are directed to “islet cells that survive without immunosuppression” and that the art of record, taken separately or together, does not teach or suggest this aspect of the invention. Applicant argues that the cited art does not teach survival without immunosuppression. Applicant states that Meissner is silent with respect to use of differentiated cells without immunosuppression. The Office disagrees. Meissner (on pages 1-2) teaches that the success of hPSC-based cell therapies may be limited by a subject’s immune response and that previous strategies, including administration of immunosuppressive drugs to the subject, have already been considered, but that novel approaches, compositions, and methods are needed for overcoming immune rejection associated with cell replacement therapies. Meissner further teaches that the disclosed universal donor stem cell-derived cell products will be immunoprivileged and will be protected from autoimmune rejection (see p. 40, lines 1-26). Accordingly, Meissner suggests cell replacement therapies that do not need the administration of immunosuppression in the subject.
Applicant argues that the Zheng and Teraoka teach away from transplanting cells in the absence of immunosuppression. The Office disagrees with Applicant’s interpretation of Zheng and Teraoka. Zheng teaches that immunosuppressive molecules such as IL-10 “may be explored”, but does not require immunosuppression. Next, Teraoka does not state that immunosuppression itself is necessary, but that glucocorticoids are necessary for immunosuppression. In fact, Teraoka explicitly suggests that immune responses to genetic manipulations affecting CD47 expression should be studied in immunocompetent animal model enabling long-term observation (see p. 7, right column, para 1). Teraoka then states: “Therefore, genetic manipulation of xenogeneic cells for host-type CD47 expression would be particularly useful to reduce the likelihood of phagocytosis by macrophages.” (see p. 7, right column, para 2). Therefore, Zheng and Teraoka do not teach away from transplanting cells in the absence of immunosuppression.
Applicant argues that the instant application teaches sufficient CD47 levels for survival for at least two weeks without immunosuppression, as evidenced by Deuse (2021. J. Exp. Med., submitted previously). Applicant argues that it would not have been “routine optimization” to determine the sufficient amount of CD47 expression required to achieve the result. Applicant relies on another reference, Deuse, to argue that CD47 delivers a threshold-dependent inhibitory signal in human NK cells, that the on off switch phenomenon either triggering rapid killing or achieving complete inhibition with no intermediate stages of NK cell or macrophage activation, and that it was unexpected that there was the similar threshold for CD47- mediated immune cell inhibition for both effector cell types. Applicant further argues that because Deuse concludes that "the threshold for CD47 expression on hiECs to inhibit innate immune cells is [about] 3.5-fold higher than the basal level." and that Figure 6A of the present application shows the threshold amount of CD47 expression was at least about 3.5-fold higher than the parental line. The Office does not find this argument persuasive because this reference was not relied upon to make the rejection of record.
Applicant argues that CD47 expression levels are not inherent in the cited art and cites MPEP 2122(IV) to state that inherence may not be established by probabilities or possibilities. Applicant further argues that the Office has not shown that the cited art discloses a sufficient amount of CD47 expression for the claimed HLA-I/HLA-II deficient cells to survive at least for two weeks without immunosuppression and that those levels are not necessarily present in the cited references. This argument is not persuasive because Meissner, Zheng, and Teraoka teach improvements to cell replacement therapies and Teraoka explicitly suggests that immune responses to genetic manipulations affecting CD47 expression should be studied in immunocompetent animal model enabling long-term observation (see p. 7, right column, para 1). Such studies would require optimization to achieve longer survival by adjusting CD47 expression levels. Applicant repeats the argument that Teraoka taught that “immunosuppressive therapy is indispensable” in xenogeneic and allogenic cellular/organ transplantation even though CD47 expression on the xenogeneic cells would be useful for reducing the likelihood of phagocytosis. However, this argument is not persuasive as discussed above. Therefore, the rejections are maintained.
Double Patenting – new necessitated by amendment
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 10, 99-102, 104-131, and 133-147 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-6, 17, 25, 40, 51, 61, 67, 69, 80, 83, 120, and 124 of copending Application No. 17607841. This new rejection is necessitated by Applicant’s amendment filed 7/25/2025 to add claims 134-147.
Copending claims 1, 4-6, 17, 25, 40, 51, 61, 67, 69, 80, 83, 120, and 124 of ‘841 application anticipate a hypoimmunogenic cell comprising one or more genetic alterations that reduce expression of functional HLA-I as compared to a parent cell and/or one or more genetic alterations that reduce expression of functional HLA-II as compared to a parent cell; one or more genetic alterations that increase expression of a functional CD47 protein as compared to the parental cell; and a safety switch, where the hypoimmunogenic cell is an islet cell. Claims 40 and 109 of the ‘841 application anticipates a modified hypoimmunogenic cell comprising HSV-tk, EC-CD, or inducible Caspase suicide gene. Claims 80 and 120 of the ‘841 application teach a modified hypoimmunogenic cell wherein the increased expression of CD47 is caused by a transgene encoding CD47 operably linked to a constitutive promoter, and wherein said increased CD47 expression causes a reduced susceptibility to NK cell killing when compared to said parent pluripotent cell. Claims 4, 17, and 83 of the ‘841 application further recite a hypoimmunogenic cell having HLA-I function reduced by a knockout of B2M, HLA-A, HLA-B, or HLA-C genes, having HLA-II function reduced by a knock out in CIITA, or HLA-DP, HLA-DR, or HLA-DQ genes.
Furthermore, the limitation “wherein the increased CD47 expression is sufficient to allow for the hypoimmunogenic cell to survive for at least 2, 4, or 6 weeks following transplantation into a subject” in instant claims 10 and 104-105 and the limitation “wherein the level of CD47 protein expressed by the hypoimmunogenic cell is at least about 3.5 fold greater than the level of CD47 protein expressed by the parental cell” in instant claim 106 is a functional limitation that is an inherent property of the increased CD47 expression lacking additional structure beyond “one or more genetic alternations that increase expression of a functional CD47 protein as compared to the parental cell”.
This is a provisional nonstatutory double patenting rejection.
Claims 10, 99-102, and 104-147 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-70 of US Patent No. 12221622. This new rejection is necessitated by Applicant’s amendment filed 7/25/2025 to add claims 134-147.
Claims 1-70 of US Patent No. 12221622 recite a hypoimmunogenic cell comprising one or more genetic alterations that reduce expression of functional HLA-I as compared to a parent cell and/or one or more genetic alterations that reduce expression of functional HLA-II as compared to a parent cell; one or more genetic alterations that increase expression of a functional CD47 protein as compared to the parental cell; and a safety switch, wherein the hypoimmunogenic cell is an islet cell. Claims 1-70 of US Patent No. 12221622 further recite a hypoimmunogenic cell wherein the increased expression of CD47 is caused by a transgene encoding CD47 operably linked to a constitutive promoter, and wherein said increased CD47 expression causes a reduced susceptibility to NK cell or macrophage killing when compared to said parent pluripotent cell. Claims 1-70 of US Patent No. 12221622 recite a hypoimmunogenic cell having HLA-I function reduced by a knockout of B2M, HLA-A, HLA-B, or HLA-C genes, having HLA-II function reduced by a knock out in CIITA, or HLA-DP, HLA-DR, or HLA-DQ genes, comprising a suicide genes HSV-tk, EC-CD, or an inducible Caspase protein.
Furthermore, the limitation “wherein the increased CD47 expression is sufficient to allow for the hypoimmunogenic cell to survive for at least 2(4,6) weeks following transplantation into a subject” in claims 10(104,105) and the limitation “wherein the level of CD47 protein expressed by the hypoimmunogenic cell is at least about 3.5 fold greater than the level of CD47 protein expressed by the parental cell” in instant claim 106 is a functional limitation that is an inherent property of the increased CD47 expression lacking additional structure beyond “one or more genetic alternations that increase expression of a functional CD47 protein as compared to the parental cell”.
Response to Arguments
Applicant's arguments filed 07/25/2025 have been fully considered but they are not persuasive. Applicant, on pages 9-10, requests withdrawal of provisional rejections over the ‘841 and ‘960 applications. The ‘960 application was issued as US Patent No. 12221622. Accordingly, a new nonstatutory double patenting rejection was made over patent ‘622 in the prior Non-Final Office Action mailed 2/25/2025. Applicant quotes MPEP 804(B)(1)(b)(i), but these NSDP rejections are not the only rejections remaining, therefore, they rejections are maintained.
Conclusion
No claim is 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 KHALEDA B HASAN whose telephone number is (571)272-0239. The examiner can normally be reached IFP, Monday - Friday 7:30am-5pm.
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, Neil Hammell can be reached at (571) 270-5919. 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.
/KHALEDA B HASAN/Examiner, Art Unit 1636
/BRIAN WHITEMAN/Primary Examiner, Art Unit 1636