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 .
Applicant’s response filed 09/29/2025 has been received and considered entered. This is a response to amendments and arguments filed 09/29/2025.
Claims Status
Claims 7, 16, 18-19 is/are cancelled and claims 24-26 is/are newly added. Claims 1-6, 8-15, 17, 20-26 is/are currently pending. Claims 1-6, 8-15, 17, 20-26 is/are under examination.
Claim Rejections - 35 USC § 112
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.
Claim 4 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 4, the phrase "preferably" in line 6 renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). This rejection is maintained.
Response to Arguments
Applicant's arguments filed 09/29/2025 have been fully considered but they are not persuasive. Applicant has argued that claim 4 was amended to remove the term “preferably”; however, no such amendment was made. As such, the rejection of claim 4 under 35 USC 112(b) is maintained.
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.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claims 1-6, 8-13, 25-26 are rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101). The above claims are directed to tissues for use as transplants. Claim 8 further is directed to a portion of an organ or of an extremity or a complete organ or extremity. These claims do not exclude tissues comprising part of a human organism as a result of transplantation (e.g. a transplanted heart in a human organism), and thus the claims encompass a human organism. As such, claims 1-13 are rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as encompassing a human organism.
Response to Arguments
Applicant's arguments filed 09/29/2025 have been fully considered but they are not persuasive.
Applicant argued that the claims are directed to genetically-manipulated tissues, and as such, it differs in its structure from a tissue found in nature (page 13). However, claims 1-6, 8-13, and 25-26 are rejected under 35 USC 101 and section 33(a) of the America Invents Act because the claims encompass tissues in human organisms, constituting part of human organisms, not because the claimed tissues are products of nature.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-6, 8-15, 17, 20-26 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Hering (WO 2016094679 A1).
Regarding claim 1, Hering teaches tissue for use as a transplant (claims 50-52, 110-112), wherein the tissue expresses allogeneic or xenogeneic MHC I and MHC II molecules (see, for example, paragraph [0036], transplants are xenografts or allografts), and expression of MHC I molecules or MHC II molecules is downregulated by 20%-99% compared to each respective molecule’s wild-type expression (claims 1, 11; paragraphs [0096]-[0097], [00119]). Hering further teaches that the tissue additionally expresses at least one complement inhibitory molecule (claim 20). Hering teaches that the tissue is not further genetically manipulated to express additional MHC I and/or MHC II (claims 1-148).
Regarding claim 2, Hering teaches that expression of the MHC I or MHC II molecules is downregulated by 20%-99% (paragraph [00119]).
Regarding claim 3, Hering teaches that the downregulation of MHC I or MHC II molecules in the tissue can be achieved by genetically modifying the tissue to comprise at least one nucleic acid construct comprising at least one expression cassette encoding inhibitory RNA, which inhibitory RNA interferes with the transcripts of the MHC I or MHC II molecules which are downregulated (paragraph [00108]).
Regarding claim 4, Hering teaches that the tissue can have reduced expression of SLA class I molecules (paragraph [0096]). Furthermore, Hering teaches that the downregulation of molecules in the tissue can be achieved by genetically modifying the tissue to comprise at least one nucleic acid construct comprising at least one expression cassette encoding inhibitory RNA, which inhibitory RNA interferes with the transcripts of the molecules which are downregulated (paragraph [00108]).
Regarding claim 5, Hering teaches that the tissue can have reduced expression of a class II transactivator gene (claim 11, MHC II transactivator CIITA). Furthermore, Hering teaches that the downregulation of molecules in the tissue can be achieved by genetically modifying the tissue to comprise at least one nucleic acid construct comprising at least one expression cassette encoding inhibitory RNA, which inhibitory RNA interferes with the transcripts of the molecules which are downregulated (paragraph [00108]).
Regarding claim 6, Hering teaches that the complement inhibitory molecules are CD46, CD55, or CD59 (claim 20).
Regarding claim 7, Hering teaches that transplantation with the genetically-modified tissues reduced the need for immunosuppression (paragraph [0036]).
Regarding claim 8, Hering teaches that the tissue is a portion of or a complete organ (claims 104-105).
Regarding claim 9, Hering teaches that expression of the MHC I or MHC II molecules is downregulated by 20%-99% (paragraph [00119]).
Regarding claim 10, Hering teaches that the expression of the MHC I or MHC II molecules is downregulated by 20%-99% (paragraph [00119]), relative to a counterpart animal, not excluding recipients of allograft transplants (paragraph [0095]).
Regarding claim 11, Hering teaches that the tissue comprises single cells, a portion of an organ, or a complete organ (claims 104-105).
Regarding claims 12 and 13, Hering teaches that expression of HLA-G in the tissue is merely optional (claim 21).
Regarding claim 14, Hering teaches a non-human mammalian animal genetically manipulated to comprise the genetically-modified tissue (claims 1, 11, 20, 50-52, 110-112; paragraphs [0036], [0096]-[0097], [00119]).
Regarding claim 15, Hering teaches a non-human animal genetically modified to express allogeneic or xenogeneic MHC I and MHC II molecules (see, for example, paragraph [0036], transplants are xenografts or allografts), and expression of MHC I molecules or MHC II molecules is downregulated by 20%-99% compared to each respective molecule’s wild-type expression (claims 1, 11; paragraphs [0096]-[0097], [00119]). Hering further teaches that the animal additionally expresses at least one complement inhibitory molecule (claim 20). Hering teaches that expression of HLA-G in the animal is merely optional (claim 21).
Regarding claim 17, Hering teaches a method of producing a tissue with reduced expression of an MHC I and an MHC II molecule (claims 1, 11; paragraphs [0096]-[0097], [00119]), expression of which molecules is reduced by 20%-99% (paragraph [00119]), the method comprising reduction of these molecules’ expression through gene editing (claims 146-147). Hering teaches that these gene editing methods can comprise utilizing siRNA (paragraph [00108]). Hering teaches that the MHC I and MHC II are allogeneic or xenogeneic for a recipient of a transplant (paragraph [0036]). Hering further teaches that the tissue is contacted with an expression cassette encoding at least one complement inhibitory molecule (claim 20; paragraph [00124]). Hering teaches that expression of HLA-G in the tissue is merely optional (claim 21).
Regarding claim 20, Hering teaches a method of treating a patient by transplanting the genetically-modified tissue (claims 110, 112). Hering teaches that treatment with the genetically-modified tissue reduces the need for chronic and generalized immunosuppression in patients having undergone tissue transplantation (paragraph [00480]).
Regarding claim 21, Hering teaches a nucleic acid construct used to genetically modify a tissue for use in transplantation (paragraph [00131]; claims 146-147), wherein the nucleic acid construct comprises at least one expression cassette encoding siRNA targeting an MHC I and an MHC II gene (paragraphs [0096]-[0097], [00108]), downregulating expression of each by 20%-99% (paragraph [00119]), and an expression cassette encoding at least one complement inhibitory molecule (paragraph [00124]). Hering also teaches that the disclosed methods and compositions can be used to “reduce a recipient’s direct immune responses, indirect immune responses, or both to a cell, tissue or organ transplanted from a donor” (paragraphs [00346], [0071]; this immune response of the recipient against the donor organ is the defining mechanism of host-versus-graft disease, or transplant rejection, see instant specification page 2 for applicant’s own definition of host-versus-graft disease).
Regarding claims 22-23, Hering teaches that the nucleic acid construct can comprise one or more nucleic acids (paragraph [00131]).
Regarding claim 24, Hering teaches that transgenes can be under the control of inducible (conditional) promoters (paragraphs [00136], [00139]). Hering teaches that the nucleic acid can comprise exogenous polynucleotides encoding regulators of complement activation (transgenes) (claim 20).
Regarding claim 25, Hering teaches that expression of HLA-G in the tissue is merely optional (claim 21).
Regarding claim 26, Hering teaches tissue for use as a transplant (claims 50-52, 110-112), wherein the tissue expresses allogeneic or xenogeneic MHC I and MHC II molecules (see, for example, paragraph [0036], transplants are xenografts or allografts), and expression of MHC I molecules or MHC II molecules is downregulated by 20%-99% compared to each respective molecule’s wild-type expression (claims 1, 11; paragraphs [0096]-[0097], [00119]). Hering further teaches that the tissue additionally expresses at least one complement inhibitory molecule (claim 20). Hering teaches that the tissue is not further genetically manipulated to express additional MHC I and/or MHC II (claims 1-148). Hering teaches that expression of HLA-G in the tissue is merely optional (claim 21).
Response to Arguments
Applicant's arguments filed 09/29/2025 have been fully considered but they are not persuasive.
Applicant argued that Hering “does not indicate nor make obvious that a specific residual expression of MHC I and of MHC II in an allogeneic or xenogeneic transplant results in an immune reaction in the recipient, which immune reaction does not result in transplant rejection, and which does not require additional expression of HLA-G in the transplant” (page 13). Hering teaches that MHC I and MHC II expression is reduced by 80-90%, as described in the rejection above. Reduced transplant rejection resulting from reduction of MHC I and/or MHC II expression between 50-90% is considered an inherent property of the reduction of MHC I and/or MHC II expression by 50-90%. As such, since Hering teaches the same reduction in MHC I and MHC II expression as is claimed by the pending claims, the tissues and methods of Hering are considered to have the same inherent properties as those recited by the pending claims. Furthermore, Hering does not require additional expression of HLA-G, and merely provides HLA-G expression as optional.
Applicant further argues that “Hering does not describe nor make obvious how a transplant tissue that expresses both allogeneic or xenogeneic MHC I and allogeneic or xenogeneic MHC II could be equipped such that in the transplant recipient an attack of immune cells against the tissue transplant is minimized or avoided without additional expression human MHC I and/or HLA-E, or without immunosuppression or treatment by tolerizing apoptotic donor cells” (page 14 of arguments), and that the examples of Hering require additional immune response suppression (page 15 of arguments). However, none of the pending claims require that the recited tissues have reduced MHC I and MHC II expression, and do not comprise HLA-E and HLA-G or any other molecule which reduces immune response. Furthermore, as discussed in the rejection above, Hering does teach that the transplanted tissues with reduced MHC I and MHC II expression reduce the requirement for additional immunosuppressant treatment.
Applicant further argues that Hering only teaches disruption of genetic expression by using CRISPR/Cas systems, and that therefore, Hering teaches reduction of gene expression by up to 100% (page 19). However, as discussed in the rejection above, Hering teaches multiple methods of reducing gene expression, including RNAi (see for example, paragraph [00108]), and teaches that gene expression can be reduced by 50-100% (see for example, paragraph [00104]), encompassing gene expression reduction of greater than 50% and less than 100%. Applicant also argues that Hering does not teach the additional expression of at least one complement inhibitor, while as discussed in the rejection above, Hering does teach the additional expression of at least one complement inhibitor.
The applicant further argues that the pending claims are non-obvious over Hering. However, the above rejection under 35 USC 102 is on the basis of anticipation, not obviousness. Arguments regarding obviousness cannot overcome a rejection based on anticipation.
For the above reasons, the rejection of pending claims under 35 USC 102 is maintained.
Double Patenting
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 1-6, 8-12, 17, 21-23, 25-26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7-14 of U.S. Patent No. 11812740 B2 in view of McGregor (2012).
~740 differs from the instant claims in that the claims of ~740 do not explicitly recite that MHC I and/or MHC II expression is downregulated by 50%-90% or 80%-90%. However, Figure 4 of the disclosure of ~740 shows that the recited invention is capable of reducing expression of MHC I and/or MHC II by 80%-90%.
Furthermore, ~740 does not recite the limitation that the methods and compositions further comprise inducing expression of a complement inhibitory molecule, such as CD55. McGregor teaches that expression of CD55 blocks “hyperacute rejection” of cardiac transplants (see title, abstract). It would have been obvious to a person of ordinary skill in the art that the recited invention of ~740 could be further augmented by the addition of a nucleic acid encoding a complement inhibitory molecule such as CD55, in order to further reduce the chance of transplant rejection.
~740 does not describe any genetic manipulation of the tissue which would result in expression of HLA-G.
Response to Arguments
Applicant's arguments filed 09/29/2025 have been fully considered but they are not persuasive. Applicant argued that the “claims in the ‘740 patent do not recite wherein expression of MHCI and MHCII is downregulated by at least 50% to up to 90%” (page 21). However, as described in the rejection above, the claimed methods are shown in the patent’s drawings to decrease MHCI and MHCII expression by at least 50% to up to 90%. As such, this degree of downregulation is an inherent property of the claimed methods.
Applicant also argued that McGregor found that expression of CD55 “did not improve graft survival” (page 1), and thus teaches against the combination of CD55 expression “with another genetic manipulation for generating a transplant that shows less rejection” (page 21 of arguments). However, McGregor teaches both that long-term survival of grafts is not affected and that hyperacute rejection is reduced by CD55 expression (page 691, “hCD55 expression contributes to the prevention of HAR, restricts vascular complement activation within the graft, but does not extend overall graft survival”). As such, the teachings of McGregor do render obvious to an artisan that increased CD55 expression can be used to reduce acute transplant rejection in the methods of ~740 directed toward reducing transplant rejection.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AFRICA M MCLEOD whose telephone number is (703)756-1907. The examiner can normally be reached Mon-Fri 9:00AM-6:00PM EST.
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/AFRICA M MCLEOD/ Examiner, Art Unit 1635
/RAM R SHUKLA/ Supervisory Patent Examiner, Art Unit 1635