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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 9/2/2025 has been entered.
Claims status
Claims 21-23, 26 is/are cancelled and claims 44-47 is/are newly added. Claims 1, 3-12, 15-20, 27-43, 44-47 is/are currently pending with claims 27-43 is/are withdrawn. Claims 1, 3-12, 15-20, 44-47 is/are under examination.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 44-47 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 44 recites the limitation "the composition" in line 1. There is insufficient antecedent basis for this limitation in the claim. For the purpose of compact prosecution, the claim(s) 44 is/are interpreted as “ing
Claim 45-47 is/are rejected due their dependence on claim 44 because they do not clarify the 112b issue noted with claim 44.
Claim Rejections - 35 USC § 112(d)
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.
Claims 11, 12, 17, 18 and 46 are rejected 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.
Claims 11 and 12 depend from claim 1 that is limited to a method using a specific cell type i.e. fibroblasts, more specifically dermal fibroblasts. Claims 11-12 recite “dedifferentiated fibroblasts” produced by dedifferentiating fibroblasts. In [0036], the specification states “The term "dedifferentiated" as used herein refers to cells possessing markers of enhanced pluripotency and plasticity subsequent to exposure to certain conditions. For example, inducible pluripotent cells are dedifferentiated forms of fibroblasts.” (emphasis added). Thus, claims 11 and 12 broaden the method of claim 1 to a method that delivers cells other than fibroblasts, such as induced pluripotent cells.
Claims 17 and 18 depend from claim 1 that is limited to a method using dermal fibroblasts i.e. fibroblasts derived from a specific tissue. Claim 17 and 18 broaden the cells delivered in the method of claim 1 to cells derived from non-dermal tissue such as tissues with regenerative properties recited in claim 18.
Claim 46 depends from claim 44 that specifically recites “fibroblast-derived microvesicles”. Claim 46 broadens the source of microvesicles to de-differentiated fibroblasts, such as induced pluripotent cells. See analysis of the term “dedifferentiated fibroblasts” presented above in the 112d rejection of claims 11 and 12.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Rejection of Claims 1, 3-10, 15-20 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the scope of enablement requirement is withdrawn because claim 1 is amended to recite a specific fibroblast type administered via specifically recited routes of administration that is supported by the specification and the prior art.
Claims 11, 12 and 46 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 enablement requirement. 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: Claims 11 and 12 as currently drafted encompass a method for reducing CRS toxicity associated with immunotherapy by administering HDAC inhibitor-treated dedifferentiated fibroblasts. Claim 46 recites a product-by-process claim wherein microvesicles derived from dedifferentiated fibroblasts are used in the method to reduce CRS toxicity.
In [0036], the specification states “The term "dedifferentiated" as used herein refers to cells possessing markers of enhanced pluripotency and plasticity subsequent to exposure to certain conditions. For example, inducible pluripotent cells are dedifferentiated forms of fibroblasts.” (emphasis added).
Therefore, claims 11 and 12 embrace a method wherein cells with enhanced pluripotency such as induced pluripotent cells are delivered to a subject. Claim 46 embraces methods wherein the microvesicles derived from cells with enhanced pluripotency such as induced pluripotent cells are delivered to a subject.
(B), (F), (G) The nature of the invention, the amount of direction and working examples provided by the applicant: The invention is in the field of suppression of cytokine-release syndrome toxicity associated with immunotherapies by administration of human dermal fibroblasts.
Applicants prophetically discloses a long list of tissue sources for the fibroblast ranging from salivary gland mucous cells to magnocellular neurosecretory cells to blood vessels and several other non-enabled sources (Page 26, 27). Regarding dedifferentiated fibroblasts, the specification teaches that "dedifferentiated fibroblasts" have enhanced pluripotency and plasticity and present inducible pluripotent cells as an example [0036]. In [0073], the specification suggests that exposure to HDAC inhibitors such as valproic acid are “capable” of inducing dedifferentiation of the fibroblasts. No evidence is provided that valproic acid, especially at the dose of 5ug/ml and exposure of 24hours used in example 1 resulted in enhanced pluripotency and/or dedifferentiated fibroblasts. Microvesicles from fibroblasts or dedifferentiated fibroblasts were neither produced nor shown to be efficacious.
In example 1, Applicants show that fibroblasts (administered intraperitoneally, source of fibroblast not stated in the specification, exposed to 5ug/ml VPA, a HDAC inhibitor, for 24 hours) block TNF increase when administered along with anti-PD11 antibody to Balb/c mice. Herein, the example does not show that exposure to 5ug/ml VPA for 24 hours dedifferentiates fibroblasts into a more “potent” cell type such as iPSC (as claimed in claims 11, 12). Critically, applicant do not teach administration of dedifferentiated fibroblasts of any type including iPSC, as recited in claims 11-12 or administration of microvesicles derived from dedifferentiated fibroblast of any type including iPSC, as recited in claim 46.
In example 2, Applicants show that HNDF (Cybrocell dermal fibroblasts which are normal human derived) reduce lethality in C57/BL6 mice injected with lymphokine activated cells via intravenous administration. These fibroblasts were not pre-treated with HDAC inhibitor as claimed in claim 1 and were not de-differentiated. Microvesicles were not separately derived or delivered.
(C), (D), (E) With respect to the state of the prior art, the level of one of ordinary skill and predictability of the art: McIntosh et al (US 7,491,388 B1, Feb.17,2009; ref of record) enables the use of human dermal fibroblasts to suppress allogenic T-cell activation that causes CRS in response to donor tissue (example 1 and 2).
Although exposure to HDAC inhibitors is known to increase transgene expression in dermal fibroblasts and can be used to increase the expression of pluripotency-inducing transcription factors (see Yasukawa et al (British Journal of Dermatology 2007 157, pp662–669; ref or record), exposure to HDAC inhibitors alone including 5ug/ml VPA for 24 hours is not known to dedifferentiate fibroblasts. Seet et al (Journal of Molecular Medicine (2019) 97:63–75; ref of record) exposed conjunctival fibroblasts to 2mM VPA for 48 hours to increase the anti-inflammatory response (Figures 5 and 6) however do not report dedifferentiation. Similarly, Sitarz et al (Molecular Genetics and Metabolism 112 (2014) 57–63; ref of record) studied the effect of VPA on human fibroblasts from POLG mutant patients that are sensitive to VPA toxicity but found that “no obvious morphological changes were observed with 5 mM VPA after 10days (see 2.2 Cell culture studies; 5mM = about 700ug/ml).
Considering cells with high pluripotency such as iPSCs are tumorigenic when injected in a subject, it is unpredictable that highly pluripotent cells such as iPSCs would reduce or enhance toxicity of any therapy. Furthermore, the art does not provide any guidance regarding microvesicles derived from cells with high pluripotency such as iPSCs and their therapeutic efficacy in reducing CRS. Thus, there is no predictability that microvesicles derived from cells with high pluripotency such as iPSCs would reduce CRS toxicity.
(H) Undue experimentation would be required to practice the invention as claimed due to the amount of experimentation necessary because of the expansive breadth of the claims, the state of the prior art and its high predictability, and the limited amount of guidance in the form of varied working examples in the specification. Neither the prior art nor the specification enable a method wherein highly pluripotent cells such as iPSCs could be delivered to a patient and wherein such cells reduce toxicity.
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 11, 12 and 46, in view of the applicant’s entire disclosure, and considering the In re Wright, In re Fisher decisions discussed above, it is concluded that the practice of the invention as claimed would not be enabled by the written disclosure. Therefore, claims 11, 12 and 46 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 practice the claimed method.
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.
Previous rejection of claim(s) 1, 3-10, 15-17, 19 and 20 under 35 U.S.C. 103 as being unpatentable over McIntosh et al (US 7,491,388 B1, Feb.17,2009; ref of record) in view of Seet et al (Journal of Molecular Medicine (2019) 97:63–75; ref of record) and Shimabukuro-Vornhagen et al (Journal for ImmunoTherapy of Cancer. (2018) 6:56; hereinafter Vornhagen; ref of record) as evidenced by Mehrotra et al (Transplantation Reviews 29 (2015) 53–59; ref of record), Gonzales et al (Dev Cell. 2017 November 20; 43(4): 387–401; ref of record), Blasi et al (Vascular Cell. 2011; 3(1):5; ref of record), Skazik et al (Experimental Dermatology, 20, 445–456; ref of record) and Fontaine et al (Life Sciences Vol. 59, No. 18, pp. 1521-1531, 1996; ref of record) is withdrawn because claim 1 is amended to recite new claim limitations. New grounds of rejection below addresses these new limitations and newly added claims.
Claim(s) 1, 3-10, 15-17, 19 and 20, 44, 45 and 47 is/are rejected under 35 U.S.C. 103 as being unpatentable over McIntosh et al (US 7,491,388 B1, Feb.17,2009; ref of record) in view of Seet et al (Journal of Molecular Medicine (2019) 97:63–75; ref of record) and Shimabukuro-Vornhagen et al (Journal for ImmunoTherapy of Cancer. (2018) 6:56; hereinafter Vornhagen; ref of record) as evidenced by Mehrotra et al (Transplantation Reviews 29 (2015) 53–59; ref of record), Gonzales et al (Dev Cell. 2017 November 20; 43(4): 387–401; ref of record), Blasi et al (Vascular Cell. 2011; 3(1):5; ref of record), Skazik et al (Experimental Dermatology, 20, 445–456; ref of record), Fontaine et al (Life Sciences Vol. 59, No. 18, pp. 1521-1531, 1996; ref of record) and new evidentiary reference Nakamura et al (Journal of Dermatological Science 84 (2016) 30–39).
Regarding claim 1, McIntosh teaches a method for reducing excess T cell immune response in graft-versus-host disease toxicity in tissue transplantation wherein the method comprises a step of intravenously administering an effective amount of dermal fibroblasts to the transplant recipient along with, before or after the therapy (Column 2, lines 1-3,8-12, 17-22, 40-50; Column 3, lines 5-7). McIntosh discloses the efficacy of their method using human normal skin fibroblasts that suppress T-cell response in a Mixed Lymphocyte reaction assay (MLR, Example 1 and 2). MLR is a common clinical assay performed prior to transplantation to measure host T-cell reactivity to donor i.e. allogenic tissue (as evidenced by Mehrotra; Table 1).
Regarding claim 17, McIntosh uses human normal skin fibroblasts i.e. fibroblasts derived from skin tissue which inherently has regenerative properties (as evidenced by Gonzales; Abstract, Conclusion, para 3).
Regarding claims 19 and 20, these are directed to the inherent properties of human skin fibroblasts taught by McIntosh. Blasi evidences that human normal dermal fibroblasts express CD105 (Results). Skazik evidences that human fibroblasts express P-glycoprotein (Figure 1) which is the protein required for rhodamine 123 efflux (evidenced by Fontaine, Abstract).
Regarding NEW claim 44, 45 and 47, McIntosh’s delivers dermal fibroblasts which inherently produce microvesicles that are derived from fibroblasts. Thus, McIntosh’s method inherently comprises delivering fibroblast-derived microvesicles. The markers recited in claim 47 are markers inherent to human dermal fibroblast-derived microvesicles, as evidenced by Nakamura (Figure 2).
Although McIntosh teaches the use of dermal fibroblasts administration to reduce unwanted T-cell response in graft-versus-host disease toxicity in tissue transplantation therapy, McIntosh does not teach application of their method to treat CRS associated with various immunotherapies recited in claims 1, 3-10. Furthermore, McIntosh does not teach treating the fibroblasts with an HDAC inhibitor prior to administration (recited in claim 1); wherein the HDAC inhibitor is VPA (recited in claim 15) and the treatment comprises 1-100ug/ml VPA for 1-72 hours (recited in claim 16).
Regarding CRS associated with various immunotherapies recited in claims 1, 3-10, Vornhagen teaches that excess T-cell activation is central to CRS (Figure 3; see feedback loop generated due to continued T-cell activation) and CRS is a common toxicity associated with various immunotherapies, such as recited in claims 1, 3-10 as well as graft-versus-host disease such as taught by McIntosh. Specifically, Vornhagen teaches CRS was observed with cancer-targeting CAR-T immunotherapies wherein the CAR-T comprises co-stimulatory domains (Table 1; as required by claims 3, 7-10). Vornhagen teaches that both antibody-based and CAR-T cell-based immunotherapies are associated with CRS (Abstract, Figure 2) and CRS was observed with immunotherapies comprising monoclonal antibodies and scFV (TGN1412, rituximab, Obinutuzumab, alemtuzumab, brentuximab, dacetuzumab, and nivolumab are monoclonal antibodies listed in Background, para 1 and blinatumomab is a BiTE molecule comprising scFV listed in Background, para 4; as required by claims 4-6). Vornhagen also teaches that CRS is reported in donor stem cell transplantation and graft-versus-host disease (= same as McIntosh; Background, para 1). Taken together, Vornhagen teaches that CRS associated with graft-versus-host disease and also CRS associated with immunotherapy (such as recited in claims 1, 3-10) function via excess T-cell activation as the central mechanism. As noted above, McIntosh teaches that their method reduces excess T cell immune response associated with graft-versus-host disease. Thus McIntosh’s method that treats CRS by targeting its central mechanism, treats CRS that may arise in association with any therapy, including immunotherapies such as recited in claims 1, 3-10.
Regarding VPA, an HDAC inhibitor, and treatment of fibroblasts with VPA, Seet teaches that fibroblasts treated with VPA have reduced expression of pro-inflammatory cytokines (VPA as required for claims 15; Figure 5, Materials and methods: Primary conjunctival fibroblast cell culture and treatments). Furthermore, Seet teaches that fibroblasts exposed to an inflammatory milieu, such as found in operated conjunctiva, participate in inflammation while treatment with VPA subdues pro-inflammatory cytokine release in both unstimulated and TNFa-stimulated fibroblasts (Figure 5, see section: VPA suppressed specific cytokine/chemokines in treated conjunctival fibroblasts). Although Seet teaches a treatment with 300ug/ml VPA for 48 hours (= claimed 1-72 hours), Seet does not teach treatment with 1-100ug/ml VPA as recited in claim 16. However, optimization of concentration and exposure duration is routine in the art. An ordinary artisan would optimize VPA concentration/duration to identify optimal working conditions to achieve desired anti-inflammatory effect. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). "It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions." In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) (see MPEP 2144.05). Therefore, in teaching treatment with 300ug/ml VPA for 48 hours, Seet renders the instantly claimed treatment conditions (1-100ug/ml VPA for 1-72 hours) prima facie obvious.
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of McIntosh to comprise VPA-pretreated fibroblasts as taught by Seet. Since, McIntosh’s method results in reduced T-cell activation, a central mechanism for CRS associated with both graft-vs-host disease as well as various immunotherapies taught by Vornhagen, an ordinary artisan reasonably expects McIntosh’s method to be applicable to treating CRS-associated with immunotherapies. Furthermore, an artisan would reasonably expect that McIntosh’s fibroblast when treated with VPA would suppress the excess T-cell activation that causes CRS (as taught by Vornhagen) while also having a subdued response to the inflammatory milieu in the CRS. This is because Seet teaches that fibroblasts release pro-inflammatory cytokines when exposed to inflammatory milieu and treatment of both unstimulated and TNFa (pro-inflammatory cytokine)-stimulated fibroblasts with VPA subdues pro-inflammatory cytokine released from fibroblasts. An ordinary artisan would be motivated to pre-treat McIntosh’s fibroblasts with VPA to reduce pro-inflammatory potential of fibroblasts when exposed to pro-inflammatory cytokines in a patient with CRS. Furthermore, since antibody-based immunotherapies, CAR-T cell-based immunotherapies for cancer and donor tissue transplantation are each associated with CRS and excessive T-cell activation is part of CRS pathophysiology, an ordinary artisan would be motivated to suppress excess T-cell activation to reduce CRS toxicity observed in antibody-based immunotherapies, CAR-T cell-based immunotherapies and donor tissue transplantation.
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.
Response to Arguments
Applicant's arguments filed 9/2/2025 regarding the U.S.C. 112a rejection of the claims 1, 3, 4-10, 15-20 and 26 have been fully considered and are persuasive (page 6, last para). However, the arguments do not address the enablement issues raised regarding claims 11 and 12 which embrace administration of “dedifferentiated fibroblasts”. Thus claims 11 and 12 remain rejected under U.S.C. 112a.
Applicant’s arguments with respect to the U.S.C. 103 rejection of claim(s) 1, 3-10, 15-17, 19, 20 have been considered but are moot because the new ground of rejection necessitated by claim amendments.
Arguments pertinent to instant U.S.C. 103 rejection of claims are addressed below.
First, Applicant argue that “Office is misapplying” Seet since “Seet describes valproic acid for use as an "anti-fibrotic therapy." Applicant's invention relates to using fibroblasts for treatment. It is unclear why a person of ordinary skill in the art would be motivated to use a method that is anti-fibroblasts. A person of ordinary skill in the art would not be motivated to treat fibroblasts with VA and then use those fibroblasts in a treatment for reducing CRS toxicity” (page 7, last para). In response, Applicants appear to confuse “anti-fibrotic” with “anti-fibroblast”. Fibrosis is excess collagen deposition by fibroblasts (see Seet Introduction, para 3) and anti-fibrotic therapies attempt to suppress specific fibroblast activities that may result in excess collagen deposition. These therapies are not “anti-fibroblasts” i.e. these therapies do not inhibit fibroblast growth or all fibroblast activity. VPA is well known as anti-inflammatory (see Seet Introduction, para 2) and VPA treatment taught by Seet allowed the fibroblasts to resist the pro-inflammatory mileu. Thus, an ordinary artisan would recognize that VPA-treated fibroblasts in McIntosh’s method would be expected to provide the benefit taught by McIntosh (i.e. reduced T-cell activation) along with the added benefit of not getting as activated by the inflammatory mileu in the patient themselves.
Next, Applicant argue that “The data demonstrate that the administration of fibroblasts cultured with an HDAC inhibitor (valproic acid) with anti-PD1L antibody can decrease excessive TNFa production (i.e., reduction in CRS toxicity), which is in line with the claimed subject matter”. In response, it must be noted that the Applicants do not argue that these data are unexpected or superior. Example 1 does not compare effect of fibroblasts with and without VPA such that criticality of treatment with VPA could be established.
Conclusion
No claim is allowed.
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