DETAILED ACTION
This action is in reply to IDS filed 10/15/2025 and papers filed 12/15/2025.
Claims 1, 4-6, 8, 17, 35, and 40 are pending and examined herein.
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 .
Election/Restrictions
Applicant’s election without traverse of Group I and Species (A), drawn to claims 1, 4-6, 8, 17, 35, and 40 in the reply filed on 07/16/2025 is acknowledged. Claims 63, 66-67, 69, 80, 83, 106, 109, and 120 are withdrawn from further as being drawn to a nonelected invention.
Withdrawn Objection(s) and Rejection(s)
The objection to the specification is withdrawn in light of the amendments to the disclosure, which removes an embedded hyperlink on p 19, para [0076].
The objection to claim 1 regarding minor informalities is withdrawn in light of the amendments to the claim.
The rejection of claims 1, 4-6, 8, 17, 35, and 40 under 35 U.S.C. 112(a) is withdrawn in light of amendments to claims 1 and 5.
The rejection of claim 1 under 35 U.S.C. 112(b) is withdrawn in light of amendments to the claim, which clarify that the modified pluripotent cell of claim 1 is a human cell.
The rejection of claim 4 under 35 U.S.C. 112(b) is withdrawn in light of deletion of the last line of the claim.
The rejection of claim 8 under 35 U.S.C. 112(b) is withdrawn in light of conjunctions added after limitations (a) and (b).
The rejection of claim 35 under 35 U.S.C. 103 as being unpatentable over Feng, as evidenced by Dean, in view of Meissner, is withdrawn in light of the amendment to claim 35, which requires that the CD47 protein has at least 90% sequence identity to SEQ ID NO: 3.
The rejection of claims 1, 4-6, 8, 17, and 35 under 35 U.S.C. 103 as being unpatentable over Focosi, as evidenced by Dean, in view of Meissner, is withdrawn in light of the amendment to claims 1 and 5 regarding the presence of the modified human pluripotent cell in a culture medium.
The rejection of claims 1, 4-6, 8, 17, and 35 under 35 U.S.C. 103 as being unpatentable over Sivalingham, as evidenced by Dean, in view of Meissner, is withdrawn in light of the amendment to claims 1 and 5 regarding the presence of the modified human pluripotent cell in a culture medium.
The rejection of claims 5 and 40 under 35 U.S.C. 103 as being unpatentable over Foscosi, in view of Meissner and Sulkowski, is withdrawn in light of the amendment to claim 5 regarding the presence of the modified human pluripotent cell in a culture medium.
The rejection of claims 5 and 40 under 35 U.S.C. 103 as being unpatentable over Sivalingham, in view of Meissner and Sulkowski, is withdrawn in light of the amendment to claim 5 regarding the presence of the modified human pluripotent cell in a culture medium.
The rejection of claims 1, 4-6, 8, 17, 35, and 40, on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 11,162,079 is withdrawn in light of the amendments to claims 1 and 5 regarding the presence of a culture medium.
The rejection of claims 1 and 5 on the ground of nonstatutory double patenting as being unpatentable over claims 26, 28, 60, and 62 of U.S. Patent No. 12,221,622079 is withdrawn in light of the amendments to claims 1 and 5 regarding the presence of a culture medium.
The rejection of claims 1, 4-6, 8, 17, 35 and 40 on the ground of nonstatutory double patenting as being unpatentable over claims 137, 140-149, and 152 of copending Application No. 17/504,502 is withdrawn in light of the amendments to claims 1 and 5 regarding the presence of a culture medium.
The rejection of claims 1 and 5-6 on the ground of nonstatutory double patenting as being unpatentable over claims 25, 52, and 54 of copending Application No. 17/792,133 is withdrawn in light of the amendments to claims 1 and 5 regarding the presence of a culture medium.
The cancellation of claim 125 renders any rejections thereof moot.
Claim Objections
Claims 1 and 5 are objected to because of the following informalities:
Claims 1 and 5 recite the phrase “a modification to an endogenous CD47 gene locus or a CD47 transgene.” For the sake of clarity, it is recommended that the phrase be amended to “a CD47 transgene or a modification to an endogenous D47 gene locus” because, as currently written, the phrase could be interpreted as “a modification to an endogenous CD47 gene locus or to a CD47 transgene.”
Claim 1 and 5 recite the limitation “fibroblast growth factor (EGF)” in the list of factors in the culture medium. The acronym for fibroblast growth factor is FGF, not EGF.
Appropriate correction is required.
Claim Interpretation
Claims 1 and 5 recite the phrase “modification to an endogenous CD47 gene locus.” The specification recites that “the term ‘modification’ refers to an alteration that physically differentiates the modified molecule from the parent molecule” (p 21, para 85). This definition is used for the purposes of examination.
Claim 4 recites the phrase “wherein the cell comprises modulated expression of.” The specification defines the term “modulated,” with respect to protein expression, as meaning that “protein expression level is increased or decreased relative to the corresponding wild type level for that protein” (p 22, para 88). This definition is used for the purposes of examination.
Claim Rejections - 35 USC § 112(b)
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 1, 4-6, 8, 17, 35, and 40 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 1 is drawn to “A modified human pluripotent stem cell” (line 1), but paragraph 3 of claim 1 recites the limitation “wherein said modified human pluripotent cell is in a culture medium.” This renders the claim indefinite, as the metes and bounds of the claim are unclear in view of the additional limitation of the culture medium. That is, it is unclear whether claim 1 is drawn to a modified human pluripotent stem cell, as recited in the preamble in line 1, or whether it is drawn to a modified human pluripotent cell in a culture medium, as recited in paragraph 3 of the claim.
The metes and bounds of claim 5 are unclear for the same reason as set forth above for claim 1. For the sake of compact prosecution, claims 1 and 5 are interpreted as being drawn to a modified human pluripotent cell in a culture medium.
Claims 4, 6, 8, 17, 35, and 40 are included in the rejection because they depend from claim 1 or 5.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 4-6, 8, 17, and 35 remain rejected under 35 U.S.C. 101 because the claimed invention is not directed to patent eligible subject matter. Based upon an analysis with respect to the claim as a whole, claim(s) 1, 4-6, 8, 17, and 35 do not recite something significantly different than a judicial exception.
Step 1: This part of the eligibility analysis evaluates whether the claim falls within any statutory category. MPEP 2106.03. Here, the claims recite a modified human pluripotent stem cell. Because a modified human pluripotent stem cell is a composition of matter, the claims fall within a statutory category. (Step 1: YES)
Step 2A, Prong One: This part of the eligibility analysis evaluates whether the claim recites a judicial exception. As explained in MPEP 2106.04(II) and the October 2019 Update, a claim “recites” a judicial exception when the judicial exception is “set forth” or “described” in the claim. Because the claims recite a nature-based product limitation, the markedly different characteristics analysis is used to determine if the nature-based product limitation is a product of nature exception. MPEP 2106.04(c)(I). MPEP 2106.04(c)(I)(A). The markedly different characteristics analysis is performed by comparing the nature-based product limitation in the claim to its naturally occurring counterpart to determine if it has markedly different characteristics from the counterpart. MPEP 2106.04(c)(II).
Here, the closest natural counterpart to the modified human pluripotent stem cell of the claims is a naturally occurring modified human pluripotent stem cell, per se.
Gross Anatomy Level
With respect to pluripotent cells, i.e. hES cells, from the vantage of gross anatomy, the art supports that hES cells are naturally occurring cells present in the inner cell mass. Specifically, the art teaches that embryonic stem cells are isolated from the inner cell mass of blastocysts. See Thomson, 1998, Science, 282: 1145-1147, 1998, at p. 1145, col. 2; p. 1145 (cited in IDS dated 10/13/23).
Cellular Level
With respect to hES cell from the vantage of the cellular level, the art teaches that hES cells are derived directly from the inner cell mass (ICM). Specifically, Reubinoff et al. (2000, Nature Biotechnology, Vol. 18, pgs. 399-404; cited in IDS dated 10/13/23) teach that the late ICM is first isolated from a human blastocyst, the isolated ICM is then plated onto a feeder layer and that within several days hES cells are present in clumps in sufficient number to be mechanically dissociated (pg. 399 col. 2 parag. 2 lines 1-9). Regarding the clumps, Reubinoff continues to teach that ICM-like clumps were removed six to eight days after initial plating of the ICM, and that these clumps propagated in a layer to form a colony of stem cells (pg. 403 col. 2 parag. 1 lines 21-25).
Molecular Level
With respect to hES cell from the vantage of the molecular level, the art teaches that hES cells may be a select subpopulation of cells isolated from the ICM. Specifically, Reijo Pera et al. (2009, Differentiation, Vol. 78, pgs. 18-23; cited in IDS dated 10/13/23) teach in Fig. 3 (reproduced below) that there are three potential pathways for the establishment of hES cells:
(i) selective expansion of a distinct subpopulation,
(ii) differentiation of epiblast cells and
(iii) reversion to pre-blastocyst stage embryonic cells.
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In the instant case, the claimed invention recites a pluripotent cell. The claims read on a human pluripotent cell, such as an ES cell or an iPS cell. With regard to the lack of certain antigens on the cells, these mutations occur naturally in the human population. With regard to an increased CD47 function that reduces susceptibility to NK cell killing, “modification to an endogenous CD47 gene locus” includes natural modifications, such as a naturally occurring mutation to the endogenous CD47 locus, which render a cell better protected from NK killing. Thus, an ICM cell in a blastocyst that is genetically blood type O-negative, is naturally occurring and amounts to the claimed pluripotent cells. Accordingly, the claims recite a judicial exception, and the analysis must therefore proceed to Step 2A, Prong Two.
Step 2A, Prong Two: This part of the eligibility analysis evaluates whether the claim as a whole integrates the recited judicial exception into a practical application of the exception. This evaluation is performed by (a) identifying whether there are any additional elements recited in the claim beyond the judicial exception, and (b) evaluating those additional elements individually and in combination to determine whether the claim as a whole integrates the exception into a practical application. 2019 PEG Section III(A)(2), 84 Fed. Reg. at 54-55.
The claims are drawn to a modified human pluripotent cell in a culture medium. The additional element of a culture medium does not integrate into the modified human pluripotent cell, and therefore does not add a meaningful limitation to the claim. The culture medium is merely a nominal or token extra-solution component of the claim and is nothing more than an attempt to generally link the product of nature to a particular technological environment. Therefore, the claim does not integrate the product into a practical application (Step 2A: NO).
Step 2B: This part of the eligibility analysis evaluates whether the claim as a whole amounts to significantly more than the recited exception, i.e., whether any additional element, or combination of additional elements, adds an inventive concept to the claim. MPEP 2106.05.
Claim 9 does not recite any elements in addition to the judicial exception of a mammalian chondrocyte progenitor cell population, so there are no additional elements that add significantly more to the judicial exception. (Step 2B: NO)
The claims are drawn to a modified human pluripotent cell in a culture medium. The presence of a culture medium does not alter the modified human pluripotent cell. The addition of a culture medium to a cell population is a well-understood, routine, and conventional activity in the art. Therefore, the claim does not include additional elements that are sufficient to amount to significantly more (also known as an “inventive concept”) than the judicial exception of a modified human pluripotent cell. (Step 2B: NO).
The claims are not patent eligible.
Rejections Necessitated by Amendments
Claim Rejections - 35 USC § 103
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.
Claims 1, 4-6, 8, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Feng (Stem Cell Reports, 2014), in view of Meissner (WO 2016/183041 A2; cited in IDS dated 10/13/23), as evidenced by Dean (Blood Groups and Red Cell Antigens, Chapter 5, 2005; cited in IDS dated 11/05/24) and STEMCELL Technologies (mTeSR™1 Product Description).
Feng teaches the generation of megakaryocytes and functional platelets from human induced pluripotent stem cells (iPSCs) (Summary). One of the human iPSC used in the experiment, RHO8, was generated using fibroblasts derived from a RH- O blood type donor (p 828, col 1, para 2) (claims 1, 5-6, 8). Dean shows that cells with blood group type O express neither the A nor B antigen (p 4, Table at top of page) (claim 1). Feng teaches knocking out the ß2-microglobulin (BM2) gene in iPSCs, rendering the cells negative for the major histocompatibility antigens HLA-A, B, and C (Summary; p 818, col 1, para 2) (claims 4, 17). HLA-A, B, and C, are MHC class I antigens (claim 1). Feng teaches culturing said iPSCs in mTeSR1 medium (p 8278, col 1, para 2), which comprises recombinant human basic fibroblast growth factor and recombinant transforming growth factor β, as evidenced by STEMCELL Technologies (p 1, “Product Description”) (claims 1, 5).
Feng does not teach a pluripotent stem cell that has reduced HLA-II function and increased CD47 function.
Meissner teaches human universal donor stem cells that are hypoimmunogenic pluripotent stem cells (p 2, para 3-4; p 4, para 3), such as embryonic stem cells (p 4, para 3), that have reduced expression of one or more MHC-I and MHC-II human leukocyte antigens (p 2, para 3) and an increased expression of CD47 (p 3, para 2-3; p 16, para 2; p 84, para 3), which are achieved by using genome editing tools such as TALEN and CRISPR systems (p 2, para 3) (claims 1, 4-5). Meissner teaches using TALEN and/or CRISPR systems to reduce expression or knock out classical MHC-I genes (HLA-A, HLA-B, and HLA-C) and MHC-II genes (e.g., CIITA) (p 2, para 3) (claims 4, 17). Meissner teaches inserting CD47 into a safe harbor locus of at least one allele of the cell to increase its expression (p 3, para 2) (claims 1, 5).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the O-negative, BM2-knockout pluripotent cells taught in Feng by using genome editing to decrease the function of MHC-II human leukocyte antigens and increase CD47 function, as taught in Meissner. One of ordinary skill in the art would have been motivated to make this modification because Feng teaches that the BM2-knockout, HLA-A, C, and C negative cells is relevant as a renewable “universal” platelet resource (p 818, col 1, para 2), and Meissner teaches that reducing the expressions of MHC-II human leukocyte antigens and increasing the expression of CD47 inhibits immune rejection in cell-based transplantation therapies (p 3, para 2-5; p 27, para 2 – p 28, para 1). One of ordinary skill in the art would have had a reasonable expectation of modifying the cells taught in Feng using the genome editing methods taught Meissner because Meissner teaches that MHC-II genes, as well as CD47, can be edited in human pluripotent stem cells.
Claims 5 and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Feng (Stem Cell Reports, 2014), in view of Meissner (WO 2016/183041 A2; cited in IDS dated 10/13/23) and Sulkowski (Int. J. Mol. Sci. 2018, 19(1), 197), as evidenced by Dean (Blood Groups and Red Cell Antigens, Chapter 5, 2005; cited in IDS dated 11/05/24) and STEMCELL Technologies (mTeSR™1 Product Description).
Claim 5 is rendered obvious over Feng, as evidenced by Dean and STEMCELL Technologies, in view of Meissner.
Regarding claim 40: Feng, in view of Meissner, does not teach the modified pluripotent cell of claim 5, further comprising a suicide gene that is activated by a trigger that causes said hypoimmunogenic pluripotent cell to die.
Sulkowski teaches induced pluripotent stem (iPS) cells comprising the exogenous suicide gene Herpes Simplex Virus Thymidine Kinase (HSV-TK), whose expression results in vulnerability of the genetically modified cells to ganciclovir (GCV) (Abstract). Sulkowski teaches that HSV-TK expressing iPS cells can be eradicated both in vitro and in vivo with high specific and efficiency with low doses of GCV, thereby increasing the safety of iPS cells for clinical applications by generating an “emergency exit” switch allowing eradication of transplanted cells (Abstract).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the modified pluripotent cell of Feng, in view of Meissner, by introducing the HSV-TK suicide gene triggered by ganciclovir, as taught in Sulkowski. One of ordinary skill in the art would have been motivated to make this modification because Sulkowski teaches that introduction of HVS-TK increases the safety of iPS cells for clinical applications. One of ordinary skill in the art would have had a reasonable expectation of successfully making this modification because Sulkowski teaches that HVS-TK can be introduced into iPS cells.
Claims 5 and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Feng (Stem Cell Reports, 2014), in view of Meissner (WO 2016/183041 A2; cited in IDS dated 10/13/23) and Jaynes (US 9,492,499 B2), as evidenced by Dean (Blood Groups and Red Cell Antigens, Chapter 5, 2005; cited in IDS dated 11/05/24) and STEMCELL Technologies (mTeSR™1 Product Description).
Claim 5 is rendered obvious over Feng, as evidenced by Dean and STEMCELL Technologies, in view of Meissner.
Regarding claim 35: Feng, in view of Meissner, does not teach the modified pluripotent cell of claim 5, wherein said CD47 protein has at least a 90% sequence identity to SEQ ID NO: 3 or said CD47 protein has the sequence of SEQ ID NO: 3. Meissner teaches inserting CD47 into a safe harbor locus of at least one allele of the human cell to increase its expression (p 3, para 2), but is silent regarding the sequence of CD47.
Jaynes teaches the amino acid sequence for human CD47, which is set forth as SEQ ID NO: 377 (col 34, lines 1-7; col 281). SEQ ID NO: 3 of the instant application (“Qy” in the alignment below) is 100% identical to the sequence set forth in SEQ ID NO: 377 of Jaynes (“Db” in the alignment below).
Query Match 100.0%; Score 1478; Length 293;
Best Local Similarity 100.0%;
Matches 293; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MWPLVAALLLGSACCGSAQLLFNKTKSVEFTFCNDTVVIPCFVTNMEAQNTTEVYVKWKF 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MWPLVAALLLGSACCGSAQLLFNKTKSVEFTFCNDTVVIPCFVTNMEAQNTTEVYVKWKF 60
Qy 61 KGRDIYTFDGALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 KGRDIYTFDGALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELT 120
Qy 121 REGETIIELKYRVVSWFSPNENILIVIFPIFAILLFWGQFGIKTLKYRSGGMDEKTIALL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 REGETIIELKYRVVSWFSPNENILIVIFPIFAILLFWGQFGIKTLKYRSGGMDEKTIALL 180
Qy 181 VAGLVITVIVIVGAILFVPGEYSLKNATGLGLIVTSTGILILLHYYVFSTAIGLTSFVIA 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 VAGLVITVIVIVGAILFVPGEYSLKNATGLGLIVTSTGILILLHYYVFSTAIGLTSFVIA 240
Qy 241 ILVIQVIAYILAVVGLSLCIAACIPMHGPLLISGLSILALAQLLGLVYMKFVE 293
|||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 ILVIQVIAYILAVVGLSLCIAACIPMHGPLLISGLSILALAQLLGLVYMKFVE 293
Given the teachings of Jaynes, there was a reasonable expectation that the human CD47 taught in Meissner and the human CD47 taught in Jaynes having the sequence set forth in SEQ ID NO: 377 would work equivalently as the sequence for a human CD47 transgene. Therefore, it would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention to have substituted the human CD47 taught in Meissner with the human CD47 having the sequence set forth in SEQ ID NO: 377 of Jaynes with predictable results. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Response to Arguments
Rejection under 35 U.S.C. § 101
Applicant argues: Applicant disagrees with the rejection but states that the present claims are directed to a modified human pluripotent cell comprising "an increased CD47 function that reduces susceptibility to NK cell killing caused by an increased expression of a CD47 protein; wherein said increased CD47 protein expression results from a modification to an endogenous CD47 gene locus or a CD47 transgene." Modification to an endogenous CD47 gene locus or a CD47 transgene are not natural phenomena, but rather, are genetic modifications made to the cell. For example, the current specification discloses several technologies for making such man-made non-natural genetic modifications such as CRISPR Technologies in paragraph [0096], TALEN Technologies in paragraph [0097], or viral based technologies in paragraph [0099]. As a result, Step 2A prong 1 is satisfied.
In response: Applicant’s arguments have been fully considered but are not persuasive. Claim 1 recites “wherein said increased CD47 protein expression results from a modification to an endogenous CD47 gene locus or a CD47 transgene.” Claims 1 and 5 do not specify that “a modification to an endogenous CD47 gene locus” is the result of human manipulation; therefore, “a modification to an endogenous CD47” encompasses natural modifications, such as a naturally occurring mutation to the endogenous CD47 locus, which render a cell better protected from NK killing.
Applicant argues: Moreover, the claims do include additional elements that integrate the judicial exception into a practical application under Step 2A prong 2. The man-made genetic modification of an endogenous CD47 gene or introducing a CD47 transgene results in practical applications of increasing CD47 protein expression. This leads to reduced susceptibility to NK cell killing. Therefore, the present claims recite genetic modifications that are "significantly more" than a judicial exception and Step 2A prong 2 is satisfied.
In response: Applicant’s arguments have been fully considered but are not persuasive. Claims 1 and 5 do not recite the language “man-made genetic modification of an endogenous CD47 gene” or its equivalent. Claims 1 and 5 merely recite “a modification to an endogenous CD47 gene locus,” the broadest reasonable interpretation of which includes naturally occurring modification without human manipulation.
Rejection under 35 U.S.C. § 103
RE: Rejection of claims 1, 4-6, 8, 17, and 35 as being unpatentable over Feng, as evidenced by Dean, in view of Meissner
Applicant argues: It was unexpectedly discovered that hypoimmunogenic pluripotent (HIP) cells and those cells differentiated from them are subject to blood type rejections during transplantation. It was thus surprising that that such blood type rejections can be avoided by matching the blood types
between the transplanted hypoimmune cells and their host.
Previously, it was known that transfusion of an ABO or Rh-incompatible red blood cell unit can lead to potentially fatal complications caused by sudden massive immune hemolysis of the transfused red blood cell, hemoglobinuria, and disseminated intravascular coagulation. At the time of this application, however, cell transplantation technologies had not taken ABO and Rh factor blood types into account. The instant application teaches for the first time that blood group antigens do in fact cause of transplanted cell rejection. (Specification at para 9.)
Applicant further points to the Specification at para 8 and WO2018/132783, as well as Specification at Examples 3 and 4 as evidence of unexpected results (see Remarks filed 12/15/2025 at pages 21-23). Applicant argues that it was a surprising result that ABO and Rh factor compatibility resulted in transplanted cell survival; that the invention teaches, for the first time, that ABO blood group and Rh factor compatibility are important for transplanted cell survival - and not just blood transfusion incompatibility. These are two separate arts altogether; that the inventors discovered that the unexpected ABO blood rejection was avoided by matching the blood types between the HIP-derived cells and their host.
Applicant argues that in contrast, Feng purportedly discloses transfusable megakaryocytes (MKs) and platelets from human induced pluripotent stem cells (iPSCs) under completely serum, animal component, and feeder-free conditions. The cells are supposedly used for increasing a patient's blood platelet count to treat conditions such as blood coagulation and dot formation. Feng supposedly generated its human iPSCs from a O- fibroblasts. Feng's MKs and platelets are supposedly useful for transfusion to treat blood-related disorders. Feng, however, merely recites what was already known in the blood transfusions arts. It does not teach or suggest the role of ABO blood type and Rh factor rejection in the completely separate regenerative medicine and cell-based cancer therapy arts. While Feng supposedly generated MKs and platelets from B2M knockout iPSCs in a small section at the end of the Results section, Feng never transfused these cells into immunocompetent mice, and in fact, nowhere teaches cell survival. At most, Feng cites a previous study that shows that B2M knockdown platelets aren't killed in immunocompromised mice when challenged with anti-HLA antibodies. This is a far cry from the long-term survival of HLA-I negative, HLA-II negative, O-, CD47 overexpressing cells in allogeneic immunocompetent recipients. This is taught for the first time in the instant specification.
In response: Applicant’s arguments have been fully considered but are not persuasive. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., the unexpected result that hypoimmunogenic pluripotent (HIP) cells and those cells differentiated from them are subject to blood type rejections during transplantation, and the long-term survival of HLA-I negative, HLA-II negative, O-, CD47 overexpressing cells in allogeneic immunocompetent recipients) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant argues: Feng's deficiencies are not cured by Dean. The Office states that Dean discloses cells with blood group type O that express neither the A nor B antigen. Dean, however, relates to "differences in our blood types that complicate blood transfusions and pregnancy ... " (Dean at p. 2.) Dean also recites nothing more than what had already been known in the art related to blood transfusions and red blood cells. It does not teach or suggest ABO blood type and Rh factor rejection of HIP-derived cells. The Office cites Meissner for teaching reduced HLA-11 function and increased CD47 function but Meissner does not teach or suggest ABO blood type or Rh factor incompatibility in hypoimmune cells. A person of ordinary skill in the art would not combine Feng with Dean and Meissner to solve the unexpected ABO blood type and Rh factor rejection of HIP-derived cells.
In response: Applicant’s arguments have been fully considered but are not persuasive. Dean is relied upon as an evidentiary reference to show that cells with blood group type O express neither the A nor B antigen. Furthermore, the limitations regarding ABO blood type and Rhesus factor phenotypes are taught in Feng.
Applicant argues: The Office has engaged in improper hindsight to combine three references. To find the claims obvious, it is not enough to simply state that the skilled artisan could have combined certain prior art references. Obviousness requires that the skilled artisan "would have been motivated to make the combinations or modifications of prior art to arrive at the claimed invention." Virtek Vision Int'l ULC v. Assembly Guidance Sys., Inc., 97 F.4th 882, 886-87 (Fed. Cir. 2024) (citing Belden Inc. v. Berk-Tek LLC, 805 F.3d 1064, 1073 (Fed. Cir. 2015). The Office has not proven that there was the requisite motivation.
A person of ordinary skill in the art would not have been motivated to combine these references and arrive at the instant invention. Feng focused on providing iPSC derived platelets for blood transfusions. Dean relates to complications with blood transfusions and red blood cells. Meisner does not teach or suggest ABO blood type or Rh factor incompatibility in cells for transplantation. Rather, the Office identified the instant claim elements, cherry-picked disjointed texts in these references, and then combined them without any evidence of the requisite motivation to combine them. The skilled artisan would have no motivation to combine these claim elements because the art was simply not aware of the blood antigen problem for transplanted cell survival. The inventors were the first to identify and then solve this problem. The rejection thus uses the instant claims as a roadmap to assemble the cited references into an obviousness rejection.
In response: Applicant’s arguments have been fully considered but are 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 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, Feng teaches O-negative, HLA-A, C, and C negative pluripotent cells, which are relevant as a renewable “universal” platelet resource (p 818, col 1, para 2), and Meissner teaches that reducing the expressions of MHC-II human leukocyte antigens and increasing the expression of CD47 inhibits immune rejection in cell-based transplantation therapies (p 3, para 2-5; p 27, para 2 – p 28, para 1). Dean is merely relied upon as an evidentiary reference to show that cells with blood group type O, as taught in Feng, express neither the A nor B antigen.
Applicant argues: The claims are now directed to a modified human pluripotent cell in a culture medium comprising one or more factors selected from the group consisting insulin-like growth factor (IGF), transforming growth factor (TGF), fibroblast growth factor (EGF), epidermal growth factor (EGF), hepatocyte growth factor (HGF), sonic hedgehog (SHH), and vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β) superfamily, bone morphogenic protein-2 (BMP2), bone morphogenic protein-7 (BMP7), a GSK3β inhibitor, an ALK inhibitor, a BMP type 1 receptor inhibitor, and retinoic acid. This claim element is not taught by the art of record.
In response: Applicant’s arguments have been fully considered but are not persuasive. As set forth in the body of the rejection above, Feng does teach the claim element (i.e., the culture medium) recited above.
RE: Rejection of claims 5 and 40 as being unpatentable over Feng, in view of Meissner and Sulkowski.
Applicant argues: Sulkowski does not cure the deficiencies of Feng and Meissner. Sulkowski teaches nothing regarding ABO and Rh matching, much less ABO blood type O and Rh negative hypoimmune cells for transplantation survival.
In response: Applicant’s arguments have been fully considered but are not persuasive. Sulkowski is relied upon for the teachings regarding a suicide gene that is activated by a trigger. The limitations regarding a human pluripotent stem cell, which is ABO blood type O and Rh negative, which are limitations set forth in claim 5, are taught in Feng.
Conclusion
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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/RISA TAKENAKA/ Examiner, Art Unit 1632
/TITILAYO MOLOYE/ Primary Examiner, Art Unit 1632