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 .
Claims status
Applicants reply filed 3/16/2026 is acknowledged.
Claims 313, 318, 331 is/are cancelled and claims 312, 314-317, 319-330, 332-340 is/are pending and is/are under examination.
Withdrawn Objections
The objections presented herein represent the full set of objections currently pending in this application. Any objections not specifically reiterated are hereby withdrawn.
Specification
Following Objection is Maintained and was not addressed by the Applicant in the reply filed 3/16/2026.
The incorporation of essential material in the specification by reference to an unpublished U.S. application, foreign application or patent, or to a publication, such as in [0177] is improper. Applicant is required to amend the disclosure to include the material incorporated by reference, if the material is relied upon to overcome any objection, rejection, or other requirement imposed by the Office. The amendment must be accompanied by a statement executed by the applicant, or a practitioner representing the applicant, stating that the material being inserted is the material previously incorporated by reference and that the amendment contains no new matter. 37 CFR 1.57(g). Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) – New, necessitated by claim amendment(s)
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.
Previous rejection of Claims 312-340 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in light of claim amendments.
Claim 319 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 319 is indefinite because it depends from a cancelled claim. Thus the meets and bounds of claim 319 cannot be determined. For the purpose of compact prosecution, the claim(s) 319 is/are interpreted as dependent from claim 312.
Claim Rejections - 35 USC § 112(d)
Improper Dependence Rejection - Moot
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Rejection of Claim 313 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends is moot due to claim cancellation.
Improper Markush Rejection – Maintained, Updated to address claim amendment
Claim 315 is rejected on the basis that they contain an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
Members of a Markush group share a "single structural similarity" when they belong to the same recognized physical or chemical class or to the same art-recognized class. A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved.
The Markush grouping of CD47, DUX4, CD24, CD27, CD46, CD55, CD59, CD200, HLA-C, HLA-E, HLA-E heavy chain, HLA-G, PD-L1, IDO1, CTLA4-Ig, C1-Inhibitor, IL-10, IL-35, IL-39, Fas1, CCL21, CCL22, MfgeS, Serpinb9, CD16 Fc receptor, ILI5-RF, CD16, CD52, H2-M3, CD35, or any combination thereof in Claim 315 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
The claimed molecules do not belong to an art-recognized class such that an expectation from the knowledge in the art was that members recited will behave in the same way in the context of the claimed invention. For example, Han et al (PNAS, Vol. 11, No. 21, May 21, 2019; IDS 1/17/2024) teaches the distinct functions of some of the claimed factors. They teach that factors such as HLA-E and HLA-G are required for tolerance from NK immune cells, while CTLA-4Ig and PD-L1 are checkpoint inhibitors wherein at least CTLA-4Ig could impair Treg function that would jeopardize immune tolerance and CD47 is taught as factor for macrophage tolerance (Introduction, para 1-3). Thus, the art identifies these factors to have distinct functions. The instant specification lists these factors as alternatives but only teaches the use of CD47 in the examples (Example 1, 2). Neither the prior art nor the instant specification teach that these alternatives are functionally equivalent such that they have a common use in the context of the claimed method, which is a method for treatment.
The claimed ‘molecule’ alternatives are not structurally similar such that they could be deemed to have a substantial structural feature and a common use that flows from the substantial structural feature. The alternatives claimed, albeit all proteins, are distinct molecules ranging from chemokines to checkpoint inhibitors to cytokine receptors that share no single structural similarity or even a substantial structural similarity that a common use, in the context of the claimed method, would flow from.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112(a)
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.
Written Description – Maintained-in-part, Updated to address claim cancellations and amendments
Rejection of Claims 313, 318, 331 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 is moot due to claim cancellation.
In the reply filed 3/16/2026, Applicant persuasively argue that sufficient description is provided for the genus of genomic modifications that reduce the cell surface expression of MHC class I/II (page 18-19, bridging para). Thus, the U.S.C. 112(a)- Written description rejection of Claims 312, 314-317, 319-330, 332-340 pertaining to ‘genomic modifications that reduce the cell surface expression of MHC class I/II’ is withdrawn.
Claims 312, 314-317, 319-330, 332-340 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 claim(s) 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.
In making a determination of whether the application complies with the written description requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is claiming and what Applicant has possession of.
Claim 312 is directed to a method of treating any disease, disorder or a condition by administering a population of hypoimmunogenic cells. The claims require the cells administered to have a specific property of “hypoimmunogenic”. However, no specific degree of hypo-immunogenicity is required such that the claims embrace a cell that is less immunogenic in comparison to any other immunogenic factor. The genus of hypoimmunogenic cells embraced by the claims comprises any cell type (such as recited in claim 317) that are modified in any way that results in the expression of CD47 to any level and genomic modifications that results in reduced expression cell surface expression of major histocompatibility complex class I (MHCI) and/or MHCII molecules.
The claims also embrace a genus of modifications that directly or indirectly result in the expression of CD47 at any level.
Regarding modifications that increase the expression of CD47 embraced by the claim, these maybe genomic or non-genomic modifications, direct to CD47 gene/protein or indirect to other genes/proteins that affect expression of CD47. For example, genomic modifications that result in the expression of an endogenous CD47 gene that directly encodes CD47, or alter the expression of another endogenous or exogenous gene that directly or indirectly results in the expression of an CD47 gene. Genomic modifications embraced could be any type of genomic modification such as substitution, insertion, deletion, frameshift etc. Non-genomic modifications embraced could comprise administering CD47 or a polypeptide that increases the expression CD47, or a non-genomically integrating vector that encodes a CD47 polypeptide or a polypeptide that increases the expression of CD47 or the like. Thus, the genus of modifications that directly or indirectly result in the expression of CD47 at any level is expansive.
Similar issues arises for claim 315 that recites increasing expression of any of the recited molecules to any level by any means.
Claims 312, 314-317, 319-330, 332-340 embrace the same genera as claim 312.
Although, the claims embrace expansive genera of hypoimmunogenic cells, modifications that directly or indirectly result in the expression of CD47 or other molecules of claim 315 at any level, the teachings in the specification are limited to a human induced pluripotent stem cell (hiPSC) wherein CD47, a macrophage-tolerizing factor, expression is increased by genomically integrating a CD47-encoding nucleotide sequence in a safe-harbor locus in addition to knockout of B2M and CIITA expression using a CRISPR-based methods to reduce the cell surface expression of MHCI and MHCII molecules and (Example 1, [00812]). These hiPSC are designated HIP cells and are shown to induce a significantly reduced immune response when transplanted subcutaneously into a rhesus monkey in comparison to control hiPSC, regardless of previous exposure to human cells by the rhesus monkey (Figure 1, 2). Similar results were obtained upon intramuscular transplantation (Example 2).
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V, v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.").”
In the instant case, only one species of hypoimmunogenic cells were reduced to practice. These are hiPSC that comprise the following genomic modifications: (i) knockout of B2M expression to reduce cell surface expression of MHCI, (ii) knockout of CIITA expression to reduce cell surface expression of MHCII, and (iii) safe-harbor insertion of CD47 encoding polynucleotide.
In para [315], the specification provides a generic disclosure for embodiments directed to cells expressing CD47 stating “In some embodiments, the present disclosure provides a method for altering a cell genome to express CD47. In some embodiments, the stem cell expresses exogenous CD47. In some instances, the cell expresses an expression vector comprising a nucleotide sequence encoding a human CD47 polypeptide. In some embodiments, the cell is genetically modified to comprise an integrated exogenous polynucleotide encoding CD47 using homology-directed repair.” In para [322], the specification envisions use of CRISPR-like gene editing systems to insert CD47 encoding sequence in a genomic locus. No other genomic modification is described.
In contrast, regarding genomic modifications to reduce MHC class I/II cell surface expression, the specification provides a variety of methods and targets, genomic and non-genomic modification; see para [230-233].
As detailed above, expansive genera are embraced by the claims with substantial variation within each genus. Disclosure of a single species cannot be considered sufficient number of representative species for such expansive genera. Considering no structure or functional characteristics that are coupled with known structural features for the variety of molecules (genes, proteins etc.) that modify the expression of CD47 or other molecules of claim 315, the specification fails to provide guidance such that it could be reasonably concluded that the inventor had possession of the claimed invention.
Therefore, the claimed invention is not adequately described. The claims require essential or critical elements which are not adequately described in the specification, and are not conventional in the art before the effective filing date. Further, the breadth of the genera embraced lack a written description.
Enablement
Rejection of Claims 313, 318, 331 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement is moot due to claim cancellation.
Previous rejection of Claims 312, 314-317, 319-330, 332-340 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement is withdrawn in light of claim amendment that narrows the scope of the claims and arguments presented in the reply filed 3/16/2026.
However, the scope embraced by the amended claims continues to lack enablement.
Claims 312, 314-317, 319-330, 332-340 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification,
while being enabling for,
A method of reducing an immune response to a cell in treatment of using the cell,
comprising administering the cellis modified:
(i) to include a nucleic acid encoding an exogenous full-length CD47, wherein the nucleic acid is inserted in a genomic locus of the cell and results in overexpression of
(ii) to include one or more genomic modifications that reduce cell surface expression of major histocompatibility complex (MHC) class I molecules, MHC class II molecules, or both, wherein the reduced cell surface expression is relative to a reference cell of the same cell type that does not comprise the one or more genomic modifications;
wherein the patient comprises memory B cells and/or memory T cells reactive against one or more alloantigens or one or more autologous antigens;
wherein the modifications (i) and (ii) to the cell render it hypoimmunogenic and the patient exhibits a reduced immune response to the cell relative to a reference cell of the same cell type that does not comprise the said modifications.
does not reasonably provide enablement for A method that can treat any disease, disorder or condition and/or wherein the cell is modified by any means to express CD47 at any level.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” See MPEP § 2164. These factors include, but are not limited to: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The office has analyzed the specification in direct accordance to the factors outlines in In re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant’s claims are not enabled.
(A) With respect to the breadth of the claims: Claim 312 as currently drafted embraces methods that treat any disease, any disorder or any condition in patient by administering a cell of any type that comprises the broadly recited structural features of (i) and (ii). Regarding the hypoimmunogenic property recited, no specific degree of hypo-immunogenicity is required nor a comparator immunogenic factor/condition is recited, thus any cell that produces a lower immune reaction in the patient in comparison to an immune reaction produced by any other immunogenic factor is embraced. Furthermore, the structural limitations recited for the cell result in the method embracing a broad array of distinct cells that could be used to treat the any disease, any disorder or any condition.
As analyzed in the U.S.C. 112a-Written Description rejection above, the genus of hypoimmunogenic cells embraced by the claims comprises any cell type that are modified in any way that results in the expression of CD47 to any level.
Thus, the first structural modification recited in (i) is broad.
Taken together, the scope of the instantly amended method of claim 312 remains broad.
Claims 316, 319-322 limit the patient but do not limit the broadly recited disease or the broadly recited hypoimmunogenic cell. Thus, the scope of claims 316, 319-322 remains broad.
Claim 314 limits the second structural modification to the hypoimmunogenic cell of claim 312 but does not limit the broadly recited disease or the broadly recited structural modification of (i) in claim 312. Thus, the scope of claim 314 remains broad.
Claim 315 adds more structural modifications to the hypoimmunogenic cell of claim 312, reciting additional molecules that could be expressed by any means and to any level. As noted in the Improper Markush rejection above, these molecules are alternatives that are expected to function equivalently in the claimed method. As noted above in U.S.C. 112a-Written Description rejection, this claim continues to embrace any type of modification, genomic or other, that could directly or indirectly result in the expression of any of the listed factors to any level. Thus, the scope of claim 315 remains expansive.
Claim 317, 323-329 limits the cell type of the hypoimmunogenic cell to a broadly recited list that includes distinct cell types and categories of cell types such as blood cells, skin cells, neural cells or any cell type that is differentiated from a stem cell. The claims embrace methods wherein an hypoimmunogenic cell of any of the recited cell types could treat any disease, disorder or condition. Thus, the scope of claim 317, 323-329 remains broad.
Claim 330, 332 recite the intended result of the claimed method without limiting the active steps of the method or the disease treated. Thus, claims 330-332 share the same broad scope of claim 312.
Claim 333-334 limit the disease/disorder/condition of claim 312 to broadly recited groups such as “a cellular deficiency” in any tissue or organ recited. Claims 335-336 limit the disease/disorder/condition of claim 312 to a range of distinct diseases such as diabetes, thyroiditis and various cancers. These claims embrace methods wherein the broadly recited hypoimmunogenic cell of claim 312 treats any of these broadly recited diseases. Thus, the scope of claims 333-334 remains broad.
Claim 338-340 recite dosing regimens for the hypoimmunogenic cells of claim 312 but do not limit the broadly recited disease or the broadly recited hypoimmunogenic cell. Thus, the scope of claims 338-340 remains broad.
(B) The nature of the invention: The invention is in the field of cell therapy, specifically on reducing the immunogenicity of cells administered for treatment.
(C) With respect to the state of the prior art: Malik et al (Regen.Med. (2019) 14(11), 983–989; IDS 1/17/2024) provides a detailed review of the literature focused on genetic engineering strategies for generating hypoimmunogenic cells. They highlight the need for generation of cells capable of evading host/patient immune response (Abstract, section “The need for universal cells”). Immune response induced in a patient upon administration of allogenic cells for a therapy is a major obstacle to clinical use of allogenic cell therapy (page 983, para 3). They discuss the three common strategies used (Figure 1). First is knockout of HLA class Ia and class II genes (HLA is human equivalent of MHC) which although successful at evading CD8+ T cell cytotoxicity become targets for NK cells cytotoxicity (see section: Engineering of HLA class Ia & II molecules). Additionally, such cells are now incapable of presenting cancer and virus-derived antigens to CD8+ T cells thus would evade CD8+ T cells even if turned cancerous or infected by virus (page 984, para 4). Solutions for at least evading NK cell cytotoxicity and also macrophage targeting in HLA class I negative cells is to express certain immunomodulatory molecules that tolerize the cells to these immune cells (see section: Engineering of immunomodulatory HLA class Ib & immune checkpoint molecules). HLA-G, HLA-E, CD47 and PD-L1 have been extensively studied as immunomodulatory molecules for this purpose(page 985, para 1, 2; Figure 1).
A number of prior art have combined these strategies to develop cells with reduced immune response (see section: How close are we to universal cells?). For example, Han taught hypoimmunogenic hiPSCs with HLA-A,B,C and CIITA knocked out and transgenic over expression of PD-L1, HLA-G and CD47 by inserting nucleic acids encoding these factors in a safe harbor genomic locus (Figure 1, 3). Deuse et al (Nature Biotechnology, Vol. 37,March 2019; IDS 1/17/2019) taught hypoimmunogenic hiPSC cells with the same modification as the instant application i.e. with a B2M and CIITA knockout and transgene overexpression of CD47 by genomic insertion of nucleic acid encoding CD47 (page 252, col. 2, para 2; Figure 1). Deuse also derive endothelial cells and cardiac cells from their modified hiPSC and show that these derived cell types remain hypoimmunogenic (Figure 2 and 3). Deuse suggest the use of these hiPSC derivatives for tissue/organ transplant (Abstract). Prior patent publications Rezania et al (WO 2020/049535 A1, 03/12/2020) using an approach similar to Deuse and derived pancreatic endodermic cells from their modified iSC generally intended for the treatment of diabetes (Example 7). Prior patent publications Nagy et al (WO 2018/227286 A1, 12/20/2018) taught immunomodulatory molecules in addition to what were taught by Malik , Han and Deuse wherein these additional molecules were specifically selected due to their ability to modulate immunosuppressive cells such as Treg and DC (Abstract; page 7, para 1, page 26-29; Table 1). Nagy used transposon based system to induce transgene expression of their immunomodulatory molecules, thus also teaching genomic insertion of nucleic acids encoding the immunomodulatory molecules (Example1).
Taken together, the prior art taught hypoimmunogenic cells with reduced cell surface expression of MHCI and MHCII molecules produced by either directly knocking out MHCI and MHCII encoding gene or by directly knocking out B2M and CIITA. Prior art also taught that reduced cell surface expression of MHCI and MHCII molecules must be combined with increased expression of other immunomodulatory molecules, specifically teaching direct transgenic over expression of specific molecules by genomically inserting nucleic acids encoding said immunomodulatory molecules. HLA-G, HLA-E, CD47 and PD-L1 being the most extensively studied immunomodulatory molecules in the prior art. Prior art also taught the use of hypoimmunogenic cells to reduce immune response associated with cell therapy-based methods of treatment.
(D) The level of one of ordinary skill in the art of generating hypoimmunogenic cells is high. An ordinary artisan routinely uses a variety of genome engineering approaches, differentiation protocols for deriving some cells types from PSCs were known, understanding of some key molecules involved in complex immune pathways was also known.
(E) With respect to the predictability of the art: Despite the success in generating hypoimmunogenic cells using the approaches discussed above and producing cells identical to the ones in the instant specification, no other hypoimmunogenic cells wherein CD47 is expressed by any means and to any level were taught in the art. Considering the expansive nature of genomic and non-genomic modifications that could directly or indirectly express CD47 to any level in a cell, a skilled artisan cannot predict which modification(s), other than direct genomic insertion of CD47 encoding nucleic acid for its overexpression, would produce the claimed hypoimmunogenic cells.
Furthermore, specifically for claim 315 that embraces additional modifications that result in expression of any of the recited molecules to any level, it remains unpredictable which one of the molecules when expressed by any means to any level would result in a hypoimmunogenic cell that can be used in a method of treating any type of disease. Malik highlights this unpredictability by noting “Which immunomodulatory molecules will prove to be safe and effective? Will the expression of one highly potent immunotolerant agent, like HLA-G, acting on multiple arms of the immune system be the optimal strategy? Or will a better approach be to knock in several immunomodulatory molecules, with each one providing protection against a specific type of immune cell? Given the immune system is highly complex, cross regulated and cascade dependent, are multiple modifications more likely to produce unpredictable and unwanted downstream immunological effects? “ (page 987, para 6).
Critically, despite the suggestion in the art, use of these cells – of the prior art or as broadly claimed, in methods of treating any disease, disorder or condition was unpredictable. A key concern raised by both Malik and Deuse is the ability of these immune-evading hypoimmunogenic cells to turn cancerous (page 984, para 4 and page 987, para 6 in Malik and page 256, col. 1 in Deuse). This is compounded by the off-target effects of CRISPR based methods which are exacerbated in the generation of these hypoimmunogenic cells that require targeting multiple genes thus increasing the risk of their oncogenic transformation (page 987, para 2 in Malik). Additionally, there is no expectation that a cell could treat any disease simply because it is hypoimmunogenic. Prior art teaches the use of hypoimmunogenic cells to reduce immune response associated with cell therapy-based methods of treatment but not to treat the disease itself.
Karpov et al (Int. J. Mol. Sci. 2023, 24, 17320) add another cause for unpredictability in the production hypoimmunogenic cell which is proper transgene expression at a level that would actually result in sufficient expression required for the cell to be hypoimmunogenic (page 19). They teach that strategies for transgene expression in universal PSC cells, specifically genomic insertion of transgene in a safe harbor location such as AAVS1 and GAPDH, by lentiviral vectors or CRISPR-based methods (page 19, para 1). However, transgene expression and efficacy in reducing immunogenicity varies depending on transgene and insertion site/means. For example, although AAVS1 locus is commonly used for transgene insertion, genes inserted in AAVS1 locus maybe silenced in certain cell types such as cells differentiated from iPSC or the transgene may not produce sufficient gene product (page 19, para 2). Another common genomic locus of GAPDH locus on the other hand appears to have transgene-specific expression level; for examples PDL1 inserted in GAPDH locus does not result in reduced immunogenicity while PDL1 inserted via lentiviral vector does (page 19, para 3). Thus, it remains unpredictable that any modification, as broadly claimed, would result in required expression of CD47 or other molecules of claim 315 necessary to render the modified cell hypoimmunogenic.
Take together, although hypoimmunogenic cells were known in the art, cells as broadly claimed were not known. Due to the lack of guidance in the art and the instant specification, it was unpredictable which modification(s) as broadly claimed, other the ones known in the prior art, would produce hypoimmunogenic cells. Use of the hypoimmunogenic cells known in the art in methods of treating a disease also remained unpredictable. Thus, it can be concluded that the use of the broadly claimed hypoimmunogenic cells in methods of treating any disease is also unpredictable.
(F), (G) With respect to the amount of direction and working examples provided by the applicant: The applicants have provided working examples directed to hypoimmunogenic cells that are the same as the prior art of Deuse. The specification teaches a human induced pluripotent stem cells (hiPSC) wherein B2M and CIITA expression is knocked out using a CRISPR-based methods to reduce the cell surface expression of MHCI and MHCII molecules and CD47, a macrophage-tolerizing factor, expression is significantly increased by genomically integrating a CD47-encoding nucleotide sequence in a safe-harbor locus (Example 1, 3, Figure 16, [00812]). These hiPSC are designated HIP cells and are shown to induce a significantly reduced immune response when transplanted subcutaneously into a rhesus monkey in comparison to control hiPSC, regardless of previous exposure to human cells by the rhesus monkey (Figure 1, 2). Similar results were obtained upon intramuscular transplantation (Example 2).
The applicants have not provided working examples generating hypoimmunogenic cells as broadly claimed. No other molecules, such as of claim 315, was tested. No other means of increasing the expression of CD47, other than direct genomic transgene insertion, was tested.
The applicants have not provided working examples using the hypoimmunogenic cells produced in a method for treating any disease, disorder or condition.
(H) Undue experimentation would be required to practice the invention as claimed due to the amount of experimentation necessary because of the broad breadth of the claims, the state of the prior art and its unpredictability, and the limited amount of guidance in the form of varied working examples in the specification. Administration of any hypoimmunogenic cell wherein CD47 is expressed by any means to any level to treat any disease is not supported by the art or the instant disclosure.
MPEP §2164.01(a), 4th paragraph, provides that, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1157, 1562; 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
After applying the Wands factors and analysis to claims 312, 314-317, 319-330, 332-340, in view of the applicant’s entire disclosure, and considering the In re Wright decision discussed above, it is concluded that the practice of the invention as claimed would not be enabled to its full scope by the written disclosure. Therefore, claims 312, 314-317, 319-330, 332-340 are rejected under 35 U.S.C. §112(a) for failing to disclose sufficient information to enable a person of skill in the art to make and use the claimed invention to its full scope.
Claim Rejections - 35 USC § 102
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.
Previous rejection of Claim(s) 312-317, 322-324, 330-335 under 35 U.S.C. 102(a)(1) as being anticipated by Schrepfer et al (WO 2020/018615 A2, 23 January 2020) is withdrawn in light of amendment to claim 132. Schrepfer does not explicitly teach a patient that exhibits memory B or T cells to an allo- or autologous antigen.
Previous rejection of Claim(s) 312-317, 322-324, 330-332 under 35 U.S.C. 102(a)(1) as being anticipated by Rezania et al (WO 2020/049535 A1, 12 March 2020) is withdrawn in light of amendment to claim 312. Rezania does not explicitly teach a patient that exhibits memory B or T cells to an allo- or autologous antigen.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claim(s) 312, 314-317, 319-324, 330, 332-335, 338-340 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rezania et al (WO 2020/049535 A1, 12 March 2020; ref of record).
Regarding claim 312, 314 and 315, Rezania teaches method for reducing an immune response to a cell in treatment of patient in need thereof with administration of universal donor cells (= hypoimmunogenic cells; [0018], [0059], [00130], [00179]). Rezania teaches universal donor cells are cells with reduced MHCI and MHCII expression, and increased expression of a tolerogenic factors [00130]. The specific modification taught include B2M and CIITA knockout and increased expression of HLA-E, HLA-G, CTLA-4, CD47, and/or PD-L1 [00136, 00137, 00139].
Regarding claim 317, 323, 324, Rezania teaches universal donor cells such mesenchymal progenitor cells (MPCs), hypoimmunogenic cardiomyocytes, muscle progenitor cells, blast cells, endothelial cells (ECs), macrophages, hepatocytes, beta cells (e.g., pancreatic beta cells), pancreatic endoderm progenitors, pancreatic endocrine progenitors, or neural progenitor cells (NPCs) derived from stem cells such as adult, pluripotent, induced pluripotent or embryonic stem cells ([00157-158). Rezania further teaches an immune system cell (e.g., megakaryocyte, microglial cell, neutrophil, mast cell, a T cell, a B cell, a Natural Killer cell) [0165].
Regarding claims 330, 332, Rezania teaches that their universal donor cells do not produce a T cell immune response and do not activate T cells killing [00376].
Regarding the patient and their immune state; such as recited in claim 312 (= claimed patient exhibits memory B or T-cells against one or more allo- or auto-antigens) and claims 316, 319-321 (= claimed causes for immune state of claim 312), Rezania does not explicitly state if the patient has the claimed immune state due to the claimed causes. However, Rezania teaches that their universal donor cells is less susceptible to allogenic rejection due to their increased immune evasion i.e. result in reduced immune activation [0059, 130]. Thus, an ordinary artisan recognizes that Rezania’s universal donor cells that evade immune response could be used to treat a patient in need, irrespective of their immune state and more importantly due to their heightened immune state because Rezania’s universal donor cells result in reduced immune activation. Furthermore, due to immune evasion properties of Rezania’s universal donor cells, they could be used to deliver a second dose of a cell therapy wherein the first dose were of cells without the immune evading properties of Rezania’s non-universal donor cell, as required for claim 322.
Similarly, regarding the specific disease the treatment is for, such as recited in claims 333-337, Rezania does not explicitly state the specific disease being treated. This is because modification taught by Rezania are to reduce immune activation of a cell used in treatment while the treatment effect is produced by the cell type itself. For example, Rezania teaches universal donor cells that are iPSCs ([00157], Examples 4, 5) and that can be differentiated into other cells types such as other progenitor or somatic cells including pancreatic endoderm cells, epithelial cells, neurons, immune system cells, blood cells etc. ([0159-165]; Example 7-9). An ordinary artisan recognizes that Rezania’s universal donor cell such as the universal donor pancreatic endoderm cell taught in Examples 7-9 would be used for a method of treatment of a pancreatic disease (as recited in claim 333) such as an autoimmune diabetes disease (as recited in claim 334-335) or to support treatment of a pancreatic cancer (as recited in claims 336-337). Similarly, an ordinary artisan recognizes that Rezania’s other universal donor cells would be useful in treatment of associated diseases.
Finally, regarding the dosing regimen of claims 338-340, wherein the hypoimmunogenic cells are administered without additional immunosuppression or after (one day or more) the transplant patient exhibits memory B or T-cells against one or more allo- or auto-antigens or at least twice separated by a period of at least one month, Rezania does not teach these dosing regimens. However, based on Rezania’s teachings regarding the ability of their universal donor cells to evade immune response, an ordinary artisan recognizes that Rezania’s universal donor cells would not require an immunosuppressive agent to be delivered before or after treatment and that Rezania’s universal donor cells could be delivered a transplant patient with heightened immune activation. Due to the reduced immune activation expected from Rezania’s universal donor cells, an ordinary artisan could repeatedly deliver these cells with a brief recovery period, such as one month recited in the claim.
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use Rezania’s universal donor cell in a method of reducing an immune response to a cell in treatment of a disease, disorder, or condition in a patient using the cell wherein the patient already comprises memory B cells and/or memory T cells reactive against one or more alloantigens or one or more autologous antigens. An ordinary artisan would be motivated to use Rezania’s universal donor cell in treating such a patient because Rezania’s universal donor cell are expected to evade patient’s immune system and produce a reduced immune response so as not to further increase the patient’s already heightened immune state. An ordinary artisan reasonably expects to use Rezania’s universal donor cell in treating such a patient by using methods known in the art, such as taught by Rezania in [0179-186].
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Claim(s) 312, 314-317, 319-324, 330, 332-335, 338-340 is/are rejected under 35 U.S.C. 103 as being unpatentable over Schrepfer et al (WO 2020/018615 A2, 23 January 2020; ref of record).
Regarding claim 312, 214, Schrepfer teaches method for reducing an immune response to a cell in treatment of patient in need thereof with administration of hypoimmune cells [0003] which are cells with reduced B2M and CIITA expression which reduced cell surface expression of MHCI and MHCII, and increased CD47 expression, a tolerogenic factor (page 3, para 1; claim 1).
Regarding claim 317, 323, 324, Schrepfer teaches hypoimmune cardiac cells, endothelial cells, neural cells, pancreatic islet cells, retinal pigment epithelial cells derived from pluripotent stem cells (page 43, 47, 52, 56, 61).
Regarding claims 330, 332, Schrepfer teaches that administration of their hypoimmunogenic cells do not produce innate immune response and do not activate NK cells, a PBMC [00194, 00329].
Regarding claim 333-335, Schrepfer teaches the following diseases related to liver, heart, lung, kidney, pancreas, brain, neural tissue, blood, bone, bone marrow, and the like [0100] comprising conditions such as neurodegenerative disease, cardiovascular disease, vascular disease [0031, 0017, 0253], more specifically Parkinson's disease, Huntington disease, and multiple sclerosis, myocardial infarction, congestive heart failure, hypertension, ischemic tissue injury [0031, 0017, 0025].
Regarding the patient and their immune state; such as recited in claim 312 (= claimed patient exhibits memory B or T-cells against one or more allo- or auto-antigens) and claims 316, 319-321 (= claimed causes for immune state of claim 312), Schrepfer does not explicitly state if the patient has the claimed immune state due to the claimed causes. However, Schrepfer teaches that their hypoimmune cell is less susceptible to allogenic rejection due to their increased immune evasion i.e. result in reduced immune activation ([102, 138, 194], Example 3). Thus, an ordinary artisan recognizes that Schrepfer’s hypoimmune cells that evade immune response could be used to treat a patient in need, irrespective of their immune state and more importantly due to their heightened immune state because Schrepfer’s hypoimmune cells result in reduced immune activation. Furthermore, due to immune evasion properties of Schrepfer’s hypoimmune cells, they could be used to deliver a second dose of a cell therapy wherein the first dose were of cells without the immune evading properties of Schrepfer’s hypoimmune cells, as required for claim 322.
Regarding the dosing regimen of claims 338-340, wherein the hypoimmunogenic cells are administered without additional immunosuppression or after (one day or more) the transplant patient exhibits memory B or T-cells against one or more allo- or auto-antigens or at least twice separated by a period of at least one month, Schrepfer does not teach these dosing regimens. However, based on Schrepfer’s teachings regarding the ability of their hypoimmune cells to evade immune response, an ordinary artisan recognizes that Schrepfer’s hypoimmune cells would not require an immunosuppressive agent to be delivered before or after treatment and that Schrepfer’s hypoimmune cells could be delivered a transplant patient with heightened immune activation. To this end, Schrepfer transplants their hypoimmune cells into the muscle of a mouse and see immune evasion and long term survival (Example 6, 8; [00348, 367]). Due to the reduced immune activation expected from Schrepfer’s hypoimmune cells, an ordinary artisan could repeatedly deliver these cells with a brief recovery period, such as one month recited in the claim.
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use Schrepfer’s hypoimmune cells in a method of reducing an immune response to a cell in treatment of a disease, disorder, or condition in a patient using the cell wherein the patient already comprises memory B cells and/or memory T cells reactive against one or more alloantigens or one or more autologous antigens. An ordinary artisan would be motivated to use Schrepfer’s hypoimmune cells in treating such a patient because Schrepfer’s hypoimmune cells are expected to evade patient’s immune system and produce a reduced immune response so as not to further increase the patient’s already heightened immune state. An ordinary artisan reasonably expects to use Schrepfer’s hypoimmune cells in treating such a patient by using methods known in the art, such as taught by Schrepfer in [16, 24, 31, 37, 44, 233, 258, 273, 287, 305].
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Claim(s) 325-329 and 336, 337 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rezania or in the alternate over Schrepfer as applied to claim 312 above, and further in view of Depil et al (‘Off- the-shelf’ allogeneic CAR T cells: development and challenges. Nat Rev: Drug Discovery; Vol. 19, March 2020).
The teachings of Rezania and Schrepfer as applied separately to claim 312 are relied upon for the instant rejection.
Both Rezania and Schrepfer teach cells that are modified to evade patient immune response and are taught to be broadly useful in cell therapy.
Both Rezania and Schrepfer teach that their hypoimmunogenic cells could be immune cells (see [157, 164] in Rezania and [0096] in Schrepfer).
Neither Rezania nor Schrepfer teach their hypoimmunogenic cells further comprising a CAR that is a first/second/third/fourth generation CAR with an antigen binding domain with a generic structure of claim 328 and that targets a generic antigen of claim 327 or specific cancer-associated antigens of claim 329.
Regarding claim 325, Depil teaches T-cells comprising CAR (Figure 1)
Regarding claim 326, Deptil teaches several designs for CARs, such as first generation CAR with antigen-biding domain and an intracellular signaling domain that would comprise the transmembrane domain, second generation CAR with additional intracellular signaling domain and third generation CAR with additional intracellular signaling domain (page 185, col. 1, para 1).
Regarding claims 327-329, Depil teaches that the CAR antigen binding domain are scfv of an antibody that targets cancer (=neoplastic cell) antigens such as listed in Table 2 which include CD19, CD22 and BCMA (page 185, col. 1, para 1).
Depil teaches that a major challenge of CAR-T cell therapy is allogenic immune reaction that can cause graft-versus host diseases in the patient and also eliminate the CAR-T cells used in therapy (page 186, col. 1, para 2).
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to further include the CARs, such as taught by Depil, in either Rezania’s or Schrepfer’s hypoimmunogenic cells wherein the cells are a T-cell. An ordinary artisan would be motivated to include a CAR in either Rezania’s or Schrepfer’s hypoimmunogenic cells because this would result in an allogenic CAR-T cell that is hypoimmunogenic and thus overcomes the challenge noted by Depil. An ordinary artisan reasonably expects to include a CAR in either Rezania’s or Schrepfer’s hypoimmunogenic cells using standard genomic approaches, taught by both Rezania (see II. Genome Editing Methods on page 16) and Schrepfer (see Methodologies for Genetic Alterations on page 28).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
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.
Previous rejection of Claims 312-317, 323-324, 334-335 as provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 196-199, 203 of copending Application No. 17/260,224 (reference application) is withdrawn in light of claim amendment.
Previous rejection of Claims 312-317, 325-329, 336, 337 as provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-6, 32, 36 of copending Application No. 17/260, 222 (reference application) is withdrawn in light of claim amendment.
Previous rejection of Claim 312-317, 323-325 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2, 4, 31 of copending Application No. 17/632,026 in view of Schrepfer et al (WO 2020/018615 A2, 23 January 2020) and Rezania et al (WO 2020/049535 A1, 12 March 2020) is withdrawn in light of claim amendment.
Previous rejection of Claims 312-317-323-326 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-3, 5, 27, 62 of copending Application No. 17/637,789 in view of Schrepfer et al (WO 2020/018615 A2, 23 January 2020) and Rezania et al (WO 2020/049535 A1, 12 March 2020) is withdrawn in light of claim amendment.
Previous rejection of Claims 312-317, 323-325, 329, 330-332, 335-340 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 268, 269-274, 282, 284, 275, 276, 285, 286-293, 294, 296 of copending Application No. 17/997,103 (reference application) is withdrawn in light of claim amendment.
Previous rejection of Claim 312-317, 335 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 20, 21, 80, 96, 198 of copending Application No. 17/907,084 (reference application) is withdrawn in light of claim amendment.
Previous rejection of Claims 312-317, 325, 326 on the ground of nonstatutory double patenting as being unpatentable over claims 1 of U.S. Patent No. 11,802,157 in view of Mohanty et al (ONCOLOGY REPORTS 42: 2183-2195, 2019), Schrepfer et al (WO 2020/018615 A2, 23 January 2020) and Rezania et al (WO 2020/049535 A1, 12 March 2020) is withdrawn in light of claim amendment.
Previous rejection of Claims 312-316, 335 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 382, 388, 392, 393, 410 of copending Application No. 18/449,625 (reference application) is withdrawn in light of claim amendment.
Previous rejection of Claim 312, 315-317, 323-325, 329 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 206, 221, 218-220 of copending Application No. 18/561,581 (reference application) is withdrawn in light of claim amendment. Claims in `581 do not recite CD47.
Previous rejection Claim 312-317, 323-325, 329 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 206, 221, 218-220 of copending Application No. 18/561,581 (reference application) is withdrawn in light of claim amendment. Claims in `581 do not recite CD47.
Previous rejection of Claims 312-317, 323, 324 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-4, 32, 33, 77 of copending Application No. 18/579148 (reference application) is withdrawn in light of claim amendment.
Previous rejection of Claims 312-316, 323, 324 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 116, 117, 213 of copending Application No. 18/682,798 (reference application) is withdrawn in light of claim amendment.
Previous rejection of Claims 312-316, 323, 324 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 116, 117, 213 of copending Application No. 18/682,782 (reference application) is withdrawn in light of claim amendments.
Previous rejection of Claims 312-315 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10, 15 of U.S. Patent No. 12,221,622 in view of Schrepfer et al (WO 2020/018615 A2, 23 January 2020) and Rezania et al (WO 2020/049535 A1, 12 March 2020) is withdrawn in light of claim amendments.
Previous rejection of Claims 312-317, 323, 324, 330-332 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 451, 460, 462, 464-466, 467-469 of copending Application No. 18/682,797 (reference application) is withdrawn in light of claim amendment.
Claims 312-317, 323-324, 334-335 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 196-199, 203 of copending Application No. 17/260,224 (reference application) in view of Schrepfer et al (WO 2020/018615 A2, 23 January 2020) and Rezania et al (WO 2020/049535 A1, 12 March 2020).
Claim 199 of `224 is a method for treating a specific disease by administering a hypoimmunogenic cell with the same structure as the instantly claimed cells of claims 312-315.
The claims in `224 do not recite a patient with memory B or T cells against allo- or auto-antigens.
However both Schepfer and Rezania teach that a cell such as of claim 199 in `224 is a hypoimmunogenic cell that results in reduced immune response to the cell ([0137-141, 178-180, 0231] in Schrepfer and [007, 0018] in Rezania; see detailed teachings from Schrepfer and Rezania in the U.S.C. 103 rejections above).
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention that the method of claim 199 of `224 can be used even when a patient has a heightened immune state such as comprising memory B or T cells against allo- or auto-antigens. Thus, claim 199 of `224 renders obvious instant claims 312-316.
The cell in the method of claim 199 of `224 is hypoimmunogenic dopaminergic cells. This meets the limitation neural cells in claims 317.
Claim 199 in `224 is a method for treating a neurodegenerative disease, specifically Parkinson, Huntington’s or multiple sclerosis recited in claim 203 of `224. This meets the limitation brain in claims 333, neurodegenerative disease in claim 334 and Parkinson, Huntington’s in claim 335.
Although claim 199 in `224 does not explicitly recite hypoimmunogenic dopaminergic cells derived from adult or pluripotent stem cells, claims 196-198 in `224 teach deriving hypoimmunogenic dopaminergic cells derived from adult or pluripotent stem cells thus rendering the instant claims 323 and 324 prima facie obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 312-317, 325-329, 336, 337 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-6, 32, 36 of copending Application No. 17/260, 222 (reference application) in view of Schrepfer et al (WO 2020/018615 A2, 23 January 2020) and Rezania et al (WO 2020/049535 A1, 12 March 2020).
Claim 32 of `222 is a method comprising administering a hypoimmunogenic T cell to a subject wherein the hypoimmunogenic T-cell is one with B2M and CIITA knocked out and CD47 expressed (recited in claim 1 of `222). The method of claim 32 of `222 is for treating cancer, as recited in claim 36 of `222.
The claims in `222 do not recite a patient with memory B or T cells against allo- or auto-antigens.
However both Schepfer and Rezania teach that a cell such as of claim 32 in `222 is a hypoimmunogenic cell that results in reduced immune response to the cell ([0137-141, 178-180, 0231] in Schrepfer and [007, 0018] in Rezania; see detailed teachings from Schrepfer and Rezania in the U.S.C. 103 rejections above).
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention that the method of claim 32 of `222 can be used even when a patient has a heightened immune state such as comprising memory B or T cells against allo- or auto-antigens. Thus, claims 1, 32 and 36 of `222 render the instant claims 312-317, 336, 337 prima facie obvious.
Claims 2-6 of `222 further teach that the claimed hypoimmunogenic T cell comprises a CAR with limitations that meet instantly claimed CAR of claims 325-329. It would be obvious to an ordinary artisan to use the hypoimmunogenic CAR-T cell of claims 2-6 of `222 in the method of cancer treatment of claim 36 of `222 to target cancer-specific antigens for the treatment of cancer.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 312-317, 323-325 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2, 4, 31 of copending Application No. 17/632,026 in view of Schrepfer et al (WO 2020/018615 A2, 23 January 2020) and Rezania et al (WO 2020/049535 A1, 12 March 2020).
Claims 4 of `026 teach a cell comprising reduced expression of MHCII and increased expression various factors that are the same in instant claim 315. Claim 2 of `026 teach a B2M and CIITA gene inactivation. Claim 31 in `026 teaches that the cell of claim could be a stem cell, a CAR-T cell, a cardiac cell, a T cell, a pancreatic cells thus meeting the limitations in instant claims 317, 323-325.
Claims in `026 do not teach using the cells of claim 1, 2, 4, 31 in a method of treating a disease in a patient with memory B or T cells against allo- or auto-antigens.
However, both Schrepfer and Rezania teach the use of cells comprising reduced expression of MHCI and II molecules as hypoimmunogenic cells used for treating a disease ([0137-141, 178-180, 0231] in Schrepfer and [007, 0018] in Rezania; see detailed teachings from Schrepfer and Rezania in the U.S.C. 103 rejections above). Thus, it would be obvious to an ordinary artisan to use the cells of `026 in a method of treating a disease.
This is a provisional nonstatutory double patenting rejection.
Claims 312-317-323-326 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-3, 5, 27, 62 of copending Application No. 17/637,789 in view of Schrepfer et al (WO 2020/018615 A2, 23 January 2020) and Rezania et al (WO 2020/049535 A1, 12 March 2020).
Claim 1-3, 5 of `789 teach cells with a reduced expression of MHCI and/or MHCII molecules such as by B2M and CIITA knockout (recited in claim 3a and 5b) and increased expression of CD24 and additional factors such as CD47 (recited in claim 3b and 5a). These cells are structurally identical to the claimed hypoimmunogenic cell of claims 312-315.
Claim 27 of `789 further teaches that the cell of claim 1 could be stem cell, a differentiated cell, a pluripotent stem cells, an induced pluripotent cells cell, a somatic cell, a T cell or a CAR-T cell. These meet the limitation in instant claims 317, 323-326.
Claim 62 in `789 teach the use of a cell comprising increased CD24 expression in a method of treating a patient.
Claims in `789 do not teach using the cells of claim 1-3, 5, 27 in a method of treating a disease in a patient with memory B or T cells against allo- or auto-antigens.
However, both Schrepfer and Rezania teach the use of cells comprising reduced expression of MHCI and II molecules as hypoimmunogenic cells used for treating a disease ([0137-141, 178-180, 0231] in Schrepfer and [007, 0018] in Rezania; see detailed teachings from Schrepfer and Rezania in the U.S.C. 103 rejections above). Thus, it would be obvious to an ordinary artisan to use the cells of `789 in a method of treating a disease.
This is a provisional nonstatutory double patenting rejection.
Claims 312-317, 323-325, 329, 330-332, 335-340 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 268, 269-274, 282, 284, 275, 276, 285, 286-293, 294, 296 of copending Application No. 17/997,103 (reference application) in view of Schrepfer et al (WO 2020/018615 A2, 23 January 2020) and Rezania et al (WO 2020/049535 A1, 12 March 2020).
Claim 268 of `103 is a method of treating a disorder in a patient comprising administering a hypoimmunogenic T cell to a subject comprising inactivation/disruption of alleles encoding MHCI or MHCII molecules i.e. reduced expression of a MHCI or MHCII molecule, and increased expression of CD47.
Claim 268 in `103 does not recite a patient with memory B or T cells against allo- or auto-antigens.
However both Schepfer and Rezania teach that a cell such as of claim 268 in `103 is a hypoimmunogenic cell that results in reduced immune response to the cell ([0137-141, 178-180, 0231] in Schrepfer and [007, 0018] in Rezania; see detailed teachings from Schrepfer and Rezania in the U.S.C. 103 rejections above).
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention that the method of claim 268 of `103 can be used even when a patient has a heightened immune state such as comprising memory B or T cells against allo- or auto-antigens. Thus claim 268 of `103 render obvious instant claims 312, 313, 316.
Claim 269-274 in `103 recite the intended result of the claimed method which are identical to the results recited in instant claims 330-332.
Claims 282 in `103 recites reducing expression of B2M and CIITA thus meeting the limitation of instant claim 314.
Claim 284 in `103 recites the same tolerogenic factors as instant claim 315.
Claims 268, 275, 276, 285 in `103 recite the dosing regimen that is the same as in instant claims 338-340.
Claims 286-293 of `103 recite the cell types recited in instant claims 317, 323-325, 329.
Claim 294 of `268 teaches cancers recited in instant claims 336 and 337.
Claims 296 in `103 teaches diabetes recited in instant claims 335.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 312-317, 335 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 20, 21, 80, 96, 198 of copending Application No. 17/907,084 (reference application) in view of Schrepfer et al (WO 2020/018615 A2, 23 January 2020) and Rezania et al (WO 2020/049535 A1, 12 March 2020).
Claim 1 and 80 in `084 is a method comprising administering neural cells with reduced expression of MHCI and/or MHCII with increased expression of CD47.
Claim 1 and 80 of ‘084 do not recite a patient with memory B or T cells against allo- or auto-antigens.
However both Schepfer and Rezania teach that a cell such as of claim 1 and 80 in `084 is a hypoimmunogenic cell that results in reduced immune response to the cell ([0137-141, 178-180, 0231] in Schrepfer and [007, 0018] in Rezania; see detailed teachings from Schrepfer and Rezania in the U.S.C. 103 rejections above).
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention that the method of claim 1, 80 of `084 can be used even when a patient has a heightened immune state such as comprising memory B or T cells against allo- or auto-antigens.
Thus claim 1 and 80 of `084 render obvious instant claim 312, 313, 315, 316, 317.
Claim 20, 21 and 96 in `084 neurological disorders such as Huntington’s, Parkinson same as instant claim 335.
Claim 198 of `084 recite reduced expression of B2M and CIITA, same as instant claim 314.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 312-317, 325, 326 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 of U.S. Patent No. 11,802,157 in view of Mohanty et al (ONCOLOGY REPORTS 42: 2183-2195, 2019), Schrepfer et al (WO 2020/018615 A2, 23 January 2020) and Rezania et al (WO 2020/049535 A1, 12 March 2020).
Claim 1 of `157 is an engineered CAR-T cell with reduced expression of B2M or CIITA, and increased expression of CD47. Thus, the cell of claim `157 has the structure of the cell used in the method of claims 312-317, 325.
Claims in `157 do not teach using the CAR-T cells. However use of CAR-T cells in cancer therapy was well known as taught by Mohanty (Abstract), and both Schrepfer and Rezania that cells with reduced expression of B2M or CIITA, and increased expression of CD47 are produced lower immune response in cell therapy (0329 in Schrepfer and 0326 in Rezania). Therefore, it would be obvious to an ordinary artisan to use the cells of claim 1 of `157 in a method for treating cancer rendering instant claims 312-315, 317, 325, 326 prima facie obvious. Further, it would be obvious to artisan that the CAR-T cells of `157 could be used to treat a patient with memory B or T cells against allo- or auto-antigens based on teachings from Schepfer and Rezania teach that a cell such as of `157 is a hypoimmunogenic cell that results in reduced immune response to the cell ([0137-141, 178-180, 0231] in Schrepfer and [007, 0018] in Rezania; see detailed teachings from Schrepfer and Rezania in the U.S.C. 103 rejections above).
Claims 312-316, 335 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 382, 388, 392, 393, 410 of copending Application No. 18/449, 625 (reference application) in view of Schrepfer et al (WO 2020/018615 A2, 23 January 2020) and Rezania et al (WO 2020/049535 A1, 12 March 2020).
Claim 410 of `625 is a method of treating diabetes by administering engineered primary islet cells produced by the method of claim 382 of `682. The dependent claims of 388, 392 and 393 in `625 teach that the islet cell produced comprises B2M and CIITA knockout by CRISPR and increased expression of CD47.
Claims of ‘625 do not recite a patient with memory B or T cells against allo- or auto-antigens.
However both Schepfer and Rezania teach that a cell such as of `625 is a hypoimmunogenic cell that results in reduced immune response to the cell ([0137-141, 178-180, 0231] in Schrepfer and [007, 0018] in Rezania; see detailed teachings from Schrepfer and Rezania in the U.S.C. 103 rejections above).
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention that the method of `625 can be used even when a patient has a heightened immune state such as comprising memory B or T cells against allo- or auto-antigens. Therefore, it is obvious to an ordinary artisan to use the cells produced by the method of claims 382, 388, 392, 393 in the method of treating diabetes recited in claim 410.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 312-317, 323, 324 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-4, 32, 33, 77 of copending Application No. 18/579148 (reference application) in view of Schrepfer et al (WO 2020/018615 A2, 23 January 2020) and Rezania et al (WO 2020/049535 A1, 12 March 2020)..
Claim 77 of `148 is a method of treating a disease by administering a cell of claim 1 that comprises reduced expression of MHCI, MHCII and increased expression of CD47.
Claims of ‘148 do not recite a patient with memory B or T cells against allo- or auto-antigens.
However both Schepfer and Rezania teach that a cell such as of `148 is a hypoimmunogenic cell that results in reduced immune response to the cell ([0137-141, 178-180, 0231] in Schrepfer and [007, 0018] in Rezania; see detailed teachings from Schrepfer and Rezania in the U.S.C. 103 rejections above).
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention that the method of `148 can be used even when a patient has a heightened immune state such as comprising memory B or T cells against allo- or auto-antigens. Therefore, claim 1 and 77 of `148 renders the instant claims 312, 313, 315-316 prima facie obvious.
Claim 2 of `148 recites cells same as instant claim 317.
Claim 3, 4 of `148 recites cells same as instant claim 323, 324.
Claim 32, 33 of `148 recites reduced B2M and CIITA expression same as instant claim 314.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 312-316, 323, 324 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 116, 117, 213 of copending Application No. 18/682,798 (reference application) in view of Schrepfer et al (WO 2020/018615 A2, 23 January 2020) and Rezania et al (WO 2020/049535 A1, 12 March 2020)..
Claim 213 of `798 is a method of treating a disease by administering a cell of claim 1 that comprises reduced expression of MHCI, MHCII due to reduced B2M and CIITA expression, and increased expression of CD47.
Claims of ‘798 do not recite a patient with memory B or T cells against allo- or auto-antigens.
However both Schepfer and Rezania teach that a cell such as of `798 is a hypoimmunogenic cell that results in reduced immune response to the cell ([0137-141, 178-180, 0231] in Schrepfer and [007, 0018] in Rezania; see detailed teachings from Schrepfer and Rezania in the U.S.C. 103 rejections above).
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention that the method of `798 can be used even when a patient has a heightened immune state such as comprising memory B or T cells against allo- or auto-antigens. Therefore, claim 1 and 213 of `798 renders the instant claims 312-316 prima facie obvious.
Claim 116, 117 of `798 recites cells same as instant claim 323, 324.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 312-316, 323, 324 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 426, 410, 413 of copending Application No. 18/682,782 (reference application) in view of Schrepfer et al (WO 2020/018615 A2, 23 January 2020) and Rezania et al (WO 2020/049535 A1, 12 March 2020)..
Claim 426 of `782 is a method of treating a disease by administering a cell of claim 410 that comprises reduced expression of MHCI, MHCII, and increased expression of a tolerogenic factor, such as CD47 recited in claim 413.
Claims of ‘782 do not recite a patient with memory B or T cells against allo- or auto-antigens.
However both Schepfer and Rezania teach that a cell such as of `782 is a hypoimmunogenic cell that results in reduced immune response to the cell ([0137-141, 178-180, 0231] in Schrepfer and [007, 0018] in Rezania; see detailed teachings from Schrepfer and Rezania in the U.S.C. 103 rejections above).
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention that the method of `782 can be used even when a patient has a heightened immune state such as comprising memory B or T cells against allo- or auto-antigens. Therefore, claim 410, 413 and 426 of `782 renders the instant claims 312, 313, 316 prima facie obvious.
Claim 413 of `782 recite the tolerogenic factors of instant claim 315.
Claim 414-415 of `782 recite reduced B2M and CIITA expression same as instant claim 314.
Claim 421, 422 of `782 recite the cells same as instant claim 317, 323, 325.
Claim 116, 117 of `798 recites cells same as instant claim 323, 324.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 312-315 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10, 15 of U.S. Patent No. 12,221,622 in view of Schrepfer et al (WO 2020/018615 A2, 23 January 2020) and Rezania et al (WO 2020/049535 A1, 12 March 2020).
Claim 1 of `622 is an hypoimmunogenic cell with reduced expression of B2M or CIITA, and increased expression of CD47. Claim 10 of `622 comprises B2M knockout while claim 15 of `622 recites CIITA knockout. Thus, the cell of claim 1, 10 and 15 of `622 have the structure of the cell used in the method of claims 312-316. Claims in `622 do not teach using the hypoimmunogenic cells in a method of treatment. However, both Schrepfer and Rezania teach that cells with reduced expression of B2M or CIITA, and increased expression of CD47 produce lower immune response in cell therapy (0329 in Schrepfer and 0326 in Rezania). They also teach that hypoimmunogenic cells can be used in methods of treatment.
Therefore, it would be obvious to an ordinary artisan to use the cells of claim 1, 10 and 15 of `622 in a method for treating a disease rendering instant claims 312-316 prima facie obvious. Further, it would be obvious to artisan that the hypoimmunogenic cells of `622 could be used to treat a patient with memory B or T cells against allo- or auto-antigens based on teachings from Schepfer and Rezania teach that a cell such as of `622 is a hypoimmunogenic cell that results in reduced immune response to the cell ([0137-141, 178-180, 0231] in Schrepfer and [007, 0018] in Rezania; see detailed teachings from Schrepfer and Rezania in the U.S.C. 103 rejections above).
Claims 312-317, 323, 324, 330-332 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 451, 460, 462, 464-466, 467-469 of copending Application No. 18/682,797 (reference application) in view of Schrepfer et al (WO 2020/018615 A2, 23 January 2020) and Rezania et al (WO 2020/049535 A1, 12 March 2020).
Claim 467-469 in `797 are methods of treating a disease using a cell of claims 464-466 which comprise the cell of claim 451 comprising reduced B2M and CIITA expression and CD47 expression.
Claims of ‘797 do not recite a patient with memory B or T cells against allo- or auto-antigens.
However both Schepfer and Rezania teach that a cell such as of `797 is a hypoimmunogenic cell that results in reduced immune response to the cell ([0137-141, 178-180, 0231] in Schrepfer and [007, 0018] in Rezania; see detailed teachings from Schrepfer and Rezania in the U.S.C. 103 rejections above).
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention that the method of `797 can be used even when a patient has a heightened immune state such as comprising memory B or T cells against allo- or auto-antigens. Therefore, claim 451, 464-466, 467-469 of `797 renders the instant claims 312-316 prima facie obvious.
Claim 460 of `797 teach the cells of instant claims 317, 323, 324.
Claim 462 of `797 recite the intended results of instant claims 330-332.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 3/16/2026 regarding the U.S.C. 112(d)- Improper Markush Rejection of clam 315 have been fully considered but they are not persuasive.
Applicants allege that “the molecules recited in the claim are all polypeptides having at least one common property” and reference a non-precedential decision Ex parte Ward, which is not part of the MPEP (page 15, last para). Of note, the copy of this decision was not attached with the reply. However, it appears that the Ward decision was for claims directed to a kit comprising antibodies for the detection of molecules that were all biomarkers for Alzheimer’s Disease and Mild Cognitive Impairment (page 16). Applicant allege that the Board referred to MPEP 2117(II)(A) and noted that the biomarkers listed in the claim at issue were all polypeptides and that the specification “provide[d] sufficient evidence” that they possess at least one property in common which is responsible for their function in the claimed invention (emphasis added; page 17, para 1). Based on this non-precedential decision, Applicant argue that the molecules of claim 315 are all polypeptides and possess a common property of “modulate the ability of a cell to be recognized by the immune system of a host” which they allege is “mainly responsible for its function in the claimed invention” (page 17, last para). Applicant point to Para 183, 315-340 and 390-404 in support.
In response, the claims at issue in Ex parte Ward do not appear analogous to the instant claims such that their pertinence to the instant rejection could be properly established. It appears that the claimed kit (a product) comprised antibodies against proteins that were shown using “sufficient evidence” to be biomarkers for a disease in the specification. The function of the Markush alternative polypeptides in those claims is that of a biomarker, such that they were deemed functionally equal in the context of a kit which simply comprised antibodies against the listed biomarkers.
However, in the instant case, the specification does not provide sufficient evidence that the recited alternatives are functionally equal in the context of the claimed method wherein the hypoimmunogenic cell comprising any of the alternatives is administered. Argument that the alternatives recited in claim 315 have a common property of “modulate the ability of a cell to be recognized by the immune system of a host” is not persuasive. This statement is from Para 183 that is a definition for immunosuppressive, immune regulatory or tolerogenic factors and does not provide evidence that each of the listed molecules function in this way in the claimed method. Paras 315-323 provide description for CD47, specifically noting its function as a “signal to circulating macrophages not to eat the cell” i.e. a factor for macrophage tolerance in [316]. This was also known in the art, for example Han discussed in the rejection. Para 324-329 provide description for CD24, specifically noting its function as an innate immune checkpoint disclosed in the cited reference to also induce macrophage tolerance [325]. However, unlike CD47 and CD24, the specification does not provide any evidence that the remainder of the molecules listed perform the alleged function. Para 330-340 provide description of DUX4 which unlike CD47 and CD24 is a transcription factor which suppresses expression of MHC class I genes [0331]. There is no description for how DUX4 modulates the ability of the hypoimmunogenic immune cells of claim 1 that comprises reduced MHC class I gene expression already. Para 390-404 list additional molecules, same as claim 315, as tolerogenic factors and recite gene editing method to insert this listed molecules in a cell’s genome however do not provide any disclosure regarding function of these molecules. Thus, unlike Ex parte Ward the specification does not “provide[d] sufficient evidence” that they possess at least one property in common which is responsible for their function in the claimed invention. Furthermore, prior art of Han was cited in the rejection that teaches that the claimed molecules are expected to not function as equivalents in the claimed method.
Applicant’s arguments, see pages 18-20, filed 3/16/2026, with respect to the U.S.C. 112(a)- Written Description rejection have been fully considered and are persuasive in part.
Applicant argue that the genus embraced by Claim 312-option (ii) that pertains to genomic modifications that reduce cell surface expression of MHC Class I and/or II molecules is supported by the disclosure, pointing to para 230-231 wherein the specification describes various targets that can be genomically modified to reduce MHC class I/II expression (page 18-19 bridging para).
This argument is persuasive. Thus, written description rejection as it pertains to Claim 312-option (ii) has been withdrawn.
However, the claims has now been amended to recite the genus embraced by Claim 312-option (i) that pertains to any modification that increases the level of CD47 to any level.
Applicant argue that disclosure, such as in para 405-447, support this genus (page 18, para 2).
This argument is not persuasive. First, para 405 are pertaining to generic methods of genomic modifications such as CRISPR or TALE-based methods. To the extent these could potentially support the instant claims, it has to be limited to genomic modifications. However, claims are not limited to genomic modification. Critically, these do not support a claim that embraces any genomic modifications that result in CD47 expression to any level. The specification is limited to direct genomic insertion of nucleic acid that directly encodes CD47 to result in an overexpression. Thus, written description rejection as it pertains to Claim 312-option (i) is maintained.
Applicant’s arguments, see pages 19-23, filed 3/16/2026, with respect to the U.S.C. 112(a)-Enablement rejection have been fully considered and are persuasive in part. The U.S.C. 112(a)-Enablement rejection has been withdrawn and a U.S.C. 112(a)- Scope of Enablement rejection is presented above.
Applicants argue that the scope of the claims has been reduced such that the claims are no more directed to the broadly claimed hypoimmunogenic cell, rather the claimed cell is modified to express CD47 and genetically modified to increase cell surface expression of MHC class I/II molecules (page 20, para 3). As for the response to the written description rejection, Applicant point to the support in the specification for genomic modifications that increase cell surface expression of MHC class I/II molecules (page 21, para 1 and 2, page 20-21, bridging para). Again as above , this portion of the argument is persuasive.
However, the claims continue to embrace any modification to the cell that expresses CD47 to any level. The support for this limitation is lacking to its full scope. A skilled artisan, based on the guidance in the specification and the prior art discussed in the rejection, would expect genomic insertion of a nucleic acid encoding CD47 to over express CD47 in the cell to have a predictable result of generating a hypoimmunogenic cell. However, the claim scope with regards to this limitation is far broader putting undue burden on the artisan to make and use the claimed cell to the full scope.
Further, Applicant argue that “the claims are not directed to the treatment of "any" disease, as alleged by the Office. The amended claims specify that the cell is administered to a patient that exhibits memory B cells and/or memory T cells reactive against one or more alloantigens or one or more autologous antigens. The instant specification indicates that the claimed cells are able to evade immune detection, and based on the guidance provided in the specification, the skilled artisan would understand that cells comprising these modifications can be administered as cellular therapies to treat a patient in need. See, as-filed application at [00812]-[00846]” (page 22, para 2).
This is not persuasive because claims specifically recite that the method is for treating a disease, disorder or a condition in a patient. Limiting the patient to one that is exhibiting some level of immune reaction to any antigen (“exhibits memory B cells and/or memory T cells reactive against one or more alloantigens or one or more autologous antigens”) does not limit the method of treatment to any specific disease. Further a list of diseases are claimed in claims 334-337. The guidance provided in the specification is limited to cells that are hypoimmunogenic cell and thus, as the Applicant notes in their response, can evade immune detection. Thus, the enabled scope is limited to “A method of reducing an immune response to a cell in treatment of using the cell” as detailed in the instant U.S.C. 112(a)- Scope of Enablement rejection.
Applicant’s arguments with respect to the U.S.C. 102 rejection of claim(s) 312-317, 322-324, 330-335 as anticipated by Schrepfer have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Applicant argue that the newly added limitation pertaining to the patient is not anticipated by the reference (page 23, para 3). However, as noted in the new U.S.C. 103 rejection of claims, Schrepfer renders obvious this new limitation.
Applicant’s arguments with respect to claim(s) the U.S.C. 102 rejection of claim(s) 312-317, 322-324, 330-335 as anticipated by Rezania have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Applicant argue that the newly added limitation pertaining to the patient is not anticipated by the reference (page 23, para 3). However, as noted in the new U.S.C. 103 rejection of claims, Rezania renders obvious this new limitation.
Applicant’s arguments with respect to claim(s) the Provisional NSDP rejection of the claims (a-m) (listed on pages 21-25) have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Of note, Applicant argues that “as provided in M.P.E.P. § 804(I)(b)(i), the Office should withdraw the rejections over reference applications 18/449,625 (August 11, 2021), 18/561,581 (May 27, 2021), 18/579,148 (July 14, 2021), 18/682,798 (August 11, 2021), 18/682,782 (August 11, 2021), and 18/682,797 (August 11, 2021), which all claim an earliest filing date that is later than the August 13, 2020 priority date of the instant application.” (page 14, para 2)
In response, since the provisional nonstatutory double patenting rejection is NOT the only rejection remaining in this application, the rejection is still proper. See M.P.E.P. § 804(I)(b)(i).
Applicant’s arguments with respect to claim(s) the NSDP rejection of the claims over claim 1 of `157 in view of Mohanty, Schrepfer and Rezania have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Applicant’s arguments with respect to claim(s) the NSDP rejection of the claims over claim 1, 10, 15 of `622 in view of Schrepfer and Rezania have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
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 MATASHA DHAR whose telephone number is (571)272-1680. The examiner can normally be reached M-F 8am-4pm (EST).
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/MATASHA DHAR/Examiner, Art Unit 1632
/EMILY A CORDAS/Primary Examiner, Art Unit 1632
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