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
Applicant’s reply filed 5/28/2026 is acknowledged.
Claims 11, 12, 15, 46 is/are cancelled. Claims 1, 3-10, 16-20, 27-43, 44, 45, 47 is/are currently pending with claims 27-43 is/are withdrawn. Claims 1, 3-10, 16-20, 44, 45 and 47 is/are under examination.
Claim Objections – New, necessitated by claim amendments
Claims 1, 17 and 18 objected to because of the following informalities: Claims are amended to recite “wherein the fibroblasts are treated with valproic acid” and also “wherein the valproic acid is exposed to the fibroblasts at a concentration of 1- 100 micrograms per milliliter.”
Since cells are exposed to chemicals and not the other way around and, ug/ml is a unit of measure for chemicals such as valproic acid, following correction is recommended: “wherein the fibroblasts are valproic acid at a concentration of 1- 100 micrograms per milliliter.” Alternatively following correction could be made: “wherein the fibroblasts are treated with valproic acid at a concentration of 1- 100 micrograms per milliliter”; “
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) – Withdrawn
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.
Rejection of Claims 44-47 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in light of claim amendment or cancellation.
Claim Rejections - 35 USC § 112(d) - Withdrawn
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 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 is withdrawn in light of claim amendment or cancellation.
Claim Rejections - 35 USC § 112(a) - Moot
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 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 is moot due to claim cancellation.
Claim Rejections - 35 USC § 103 – New, necessitated by claim amendments
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.
Rejection of Claim(s) 1, 3-10, 15-17, 19 and 20, 44, 45 and 47 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) is withdrawn to address the newly added claim amendments to claim 1, 17 and 18.
Claim(s) 1, 3-10, 16-20, 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 Nakamura et al (Journal of Dermatological Science 84 (2016) 30–39; ref of record).
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 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 claims 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 1-100ug/ml valproic acid prior to administration (recited in claim 1) for 1-72 hours (recited in claim 16) or 1-75ug/ml for 24 hours (recited in claim 17) or about 5ug/ml for about 24 hours (recited in claim 18).
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 and treatment of fibroblasts with VPA, Seet teaches that fibroblasts treated with VPA have reduced expression of pro-inflammatory cytokines (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 in claim 16), Seet does not teach treatment with 1-100ug/ml VPA as recited in claim 1, 16 or 1-75ug/ml for 24 hours as recited in claim 17 or about 5ug/ml for about 24 hours as recited in claim 18. 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 VPA that reduces release of pro-inflammatory cytokines from fibroblasts, Seet renders the instantly claimed treatment conditions as required by claims 1, 16-18 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. An ordinary artisan would use routine optimization method to identify the optimal concentration and duration of VPA exposure. 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 with respect to the U.S.C. 103 rejection of claim(s) 1, 3-10, 15-17, 19, 20, 44, 45, and 47 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.
Applicant argue that the amended claims are patentable over the cited art because the amended claims recite a concentration range for VPA which is “critically different from that used in Seet” (page 9, para 2). Applicant note that Seet’s concentration is three times higher than the claimed upper limit (page 9, para 3) and allege that “the claimed concentration range of 1-100 μg/ml is not an optimization of Seet's 300μg/ml concentration, but rather is a substantially different concentration range that falls entirely outside the concentration used in Seet. Routine optimization contemplates adjustments within or proximate to a disclosed range, not departures to entirely different concentration regimes” (page 9, para 4). Applicant point to example 1 that show “fibroblasts treated with 5 μg/ml VPA for 24 hours were effective in blocking TNF increase when administered along with anti- PD-1 antibody, demonstrating reduction of CRS toxicity. The prior art provides no suggestion that such dramatically lower concentrations would be effective” (page 9-10, bridging para).
In response, there is no evidence that the recited concentration range is critical. Example 1 that used 5ug/ml VPA for 24 hours (recited in claim 18) does not compare effect of fibroblasts with and without VPA such that criticality of treatment with VPA could be established. Per McIntosh, even fibroblasts without VPA exposure are result effective. There is no showing that VPA exposure, at any concentration or duration, resulted an unexpected and/or superior outcome.
Routine optimization is not restriction to adjustments within or proximate to a disclosed range. MPEP 2144.05 states “Optimization Within Prior Art Conditions or Through Routine Experimentation” and “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[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); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.")”. Thus, alleged “substantial difference” in concentration of Seet and the instant disclosure is not shown to lend a patentable distinction. Seet provides the teaching and suggestion to exposure fibroblast to VPA. An ordinary artisan could identify optimum concentration and/or duration of exposure using routine methods. Identifying lowest concentration and duration of exposure is generally desirable since it reduces costs, experimentation time and potential off-target effects. Thus, following Seet’s teaching and suggestion and using routine optimization, an ordinary artisan would identify the lowest concentration and duration of VPA exposure that is results in desired effects.
Regarding Seet, Applicant argue that “ Seet teaches a specific VPA concentration (300 μg/ml) for a specific purpose (reducing collagen deposition in post-operative conjunctiva), which is distinct from the claimed method of reducing CRS toxicity associated with immunotherapy” (page 10, para 1).
In response, Seet teaches VPA exposure to reduce inflammation and shows the effects of VPA-exposed fibroblast on cytokine release (Figure 5, 6) and concludes “Since VPA can subdue proinflammatory cytokine secretion by uninduced fibroblasts, this drug may potentially be helpful for preempting inflammation when applied pre-operatively, on top of intra- and post-operative administration” (page 69, col. 2, para 1). Thus, Seet is not limited to reducing collagen deposition in post-operative conjunctiva but provides a teaching pertinent to instant claims, specifically regarding reducing proinflammatory cytokine secretion by uninduced fibroblasts when injected into a patient with inflammation.
Applicant allege “unexpected results at the claimed concentrations demonstrates criticality of that range” because “fibroblasts treated with VPA at concentrations within the claimed range (specifically, 5μg/ml) are effective in reducing CRS toxicity.” (page 10, para 2)
In response, data showing that a concentration is result effective does not necessarily support the allegation of unexpected results. There is no evidence that an ordinary artisan did not expect fibroblasts treated with VPA at concentrations within the claimed range (specifically, 5μg/ml) to be result ineffective such that the disclosed results could be considered unexpected. Per McIntosh, even fibroblasts without VPA exposure are result effective. As noted above, Example 1 that used 5ug/ml VPA for 24 hours (recited in claim 18) does not compare effect of fibroblasts with and without VPA such that criticality or superiority of treatment with VPA could be established. Furthermore, only a single concentration was tested thus there is no evidence that even if the specific concentration was superior that this applies to the entire claimed range.
Applicant allege lack of motivation “to reduce the VPA concentration from Seet's 300μg/ml to the claimed range while expecting the same or similar anti-inflammatory effect.” (page 10, para 3).
In response, see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.")”. (MPEP 2144.05). Thus, motivation to reduce VPA concentration from Seet's 300μg/ml to the claimed range is present as a normal desire of artisans.
Regarding Nakamura, McIntosh and Shimabukuro-Vornhagen, Applicant argue that these do not cure the deficiency of Seet (page 10, 11).
In response, arguments pertaining to Seet were not persuasive. Thus, this argument is not persuasive.
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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