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 .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
DETAILED ACTION
This action is in response to claim amendments filed 4/22/26. Claims 1-6, 8-11, 14, 17-18, 23-24, 32-33, 41, and 62 are pending.
Applicant’s election of Group I (method of treating cancer) and the species of cell comprising a polynucleotide, vector introduced into dendritic cell, lentiviral vector, PD-1 inhibitor, pembrolizumab, and autologous without traverse in the reply filed on 7/28/25 remains in effect.
Claim 62 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 4, 6, 8, 11, are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 1-3, 5, 9-10, 14, 17-18, 23-24, 32-33, and 41 are under examination.
Withdrawn
The §112b rejections are withdrawn in light of the amendment. The terms “high”, “low”, and the phrases with insufficient antecedent basis have been removed. Further, the claims no longer recite the data being “used”.
The §112a rejection is withdrawn in light of the amendment. The claims no longer recite the data being “used” to make decisions.
Maintained Rejections and New Rejections Necessitated by Amendment
Specification
The disclosure is objected to because of the following informalities: The “sum” column in the top table on page 40 is incorrect; 11%+52% is 63%.
Appropriate correction is required.
Claim Objections
Claim 5 objected to because of the following informalities: the list contains two “and”s, one in line 3 and one in line 5. There should only be one conjunction in a single list. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 32 and 41 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.
Claims 32 and 41 contain the trademark/trade name Foudantionone CDXtm, Foundationone®, FoundationAct®, and Foundationone®Heme. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a type of assay and by extension claim limitations regarding the steps and elements required to perform the diagnostic assay. Neither the claims nor the specification set forth any specific steps or elements required by these assays nor does the specification set forth the generic terminology. By defining these solely by the source of the assay rather than a generic assay or any specific steps/elements, others could not fairly determine what is or is not required of the claim. Accordingly, the identification/description is indefinite.
Therefore, claims 32 and 41 are indefinite.
Claim 23 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 23 recites the limitation "the CXCL9 polypeptide" in line 1 among other such recitations. There is insufficient antecedent basis for this limitation in the claim. Claim 1 was amended to remove the polypeptides and polynucleotide options, leaving only the cell option. Claim 23 has not been similarly amended and now references limitations that are no longer present and so lack antecedent basis.
Therefore, claim 23 is indefinite.
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.
Claims 1-3, 5, 9-10, 14, 17-18, 23-24, 32-33, and 41 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 achieving synergistic effects with RMP-1-14 in combination with dendritic cells expressing either CXCL9, CXCL10, or both when administered simultaneously and the cells are administered intratumorally, does not reasonably provide enablement for other PD-1 inhibitors, non PD-1 inhibitors such as PD1-L1 inhibitors, or CDCL9 and/or CDCL10 administered in ways other than via dendritic cell expression administered intratumorally or when delivered separately from the checkpoint inhibitor at different times. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are many factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue. These factors include, but are not limited to: 1) nature of the invention, 2) breadth of claims, 3) amount of direction or guidance by the inventor, 4) relative skill of those in the art, 5) level of predictability in the art, 6) state of the prior art, 7) existence of working examples, and 8) quantity of the experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)
The nature of the invention is a cancer treatment. As amended, the breadth of the claims is limited to combinations of therapeutics that explicitly generate “synergistic anti-tumor effects”. As characterized by Applicant, combination of “cells expressing CXCL9/CXCL10 and an immune checkpoint inhibitor provides an unexpectedly better outcome” (remarks 4/22/26 p.9). This statement is not commensurate with what has been demonstrated but taking the statement at face value supports the conclusion that making and testing each of the claimed combinations that have not been reduced to practice amounts to an unpredictable effort on the part of others and therefore undue experimentation.
The specification combines RMP-1-14 (an anti-mouse PD-1 antibody) with CXCL9-DC, CXCL10-DC, or CXCL9/10-DC; see pages 36, 37, 39, 40, and 41. In all of these tables, the combination of the anti-PD-1 with the CXCL produces a greater than additive effect. However:
The examples administer both therapeutics at the same time (“in combination”; p.38) while claim 1 has no such limitation (there are two separate “administration” steps which may be separated by any amount of time).
The “anti-PD-1” administered in the examples is the anti-mouse PD-1 antibody RMP-1-14 (paragraph 130) while claim 1 covers any PD-1 inhibitor or specifically the eighteen (18) inhibitors in claim 5, none of which are RMP-1-14 and all of which are antibodies.
The examples deliver the CXCL9 or 10 via a dendritic cell (DC) while claim 1 covers any possible cell.
The examples deliver the DCs intratumorally while claim 1 covers any possible administration route.
Thus, while Applicant’s position is that the “unexpectedly better outcome” applies to any checkpoint inhibitor and the claims cover a myriad of permutations, Applicant’s support for such synergy is quite narrow. Per MPEP §716.02(a), greater than expected results are evidence of non-obviousness. Specifically, “Evidence of a greater than expected result may also be shown by demonstrating an effect which is greater than the sum of each of the effects taken separately (i.e., demonstrating “synergism”). Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989)”. Such is the case here, where the objective evidence is such that certain combinations produce a greater reduction in tumor volume than merely summing the individual effects. Applicant has alleged these unexpected results, which also confers the burden to Applicant to establish that the results are unexpected commensurate in scope with the claims (MPEP §716.02(b and d)).
Applicant has the burden of explaining the proffered data (MPEP §716.02(b)(II)), but has not explained any reasoning to expect that administering other PD-1, PD1-L1, or PD1-L2 inhibitors would produce the same synergy. Unexpected results are, by their nature, unpredictable. While a claim to a genus may be supported by data showing the unexpected property of a species, it is further Applicant’s burden to provide evidence that would allow “one of ordinary skill in the art…to determine a trend in the exemplified data which would allow the artisan to reasonably extend the probative value thereof” (MPEP §716.02(d)). The disclosure of a single mouse antibody does not support the breadth of all PD-1 antibodies which may bind different epitopes and inhibit in different ways, nor does this support non-antibodies (such as small molecules or siRNA) or inhibiting targets other than PD-1.
The above MPEP sections are set forth with respect to overcoming a §103 rejection on the basis of unexpected results. These sections are relevant to enablement because Applicant is not only attempting to overcome the previous §103 rejection but has amended the claims to require synergy. The claims therefore require the person of the art to be able to make and use—to obtain the claimed synergy—without undue experimentation while the evidence and arguments are such that these results are unpredictable.
Regarding point 1, all of the examples administer both the checkpoint inhibitor and the CXCL at the same time; however, the claim allows for the therapeutics to be administered minutes, days, or even months apart. There is no scientific reason to expect synergy between two drugs to be demonstrated when one is administered after the first has already left the system of the patient and so it is left to others to determine the timing and dosing schedules that result in the claimed synergy despite said synergy being “unexpected” and therefore unpredictable. There is insufficient objective evidence for the person of ordinary skill in the art to determine a trend regarding the timing as only a single timing—simultaneous—has been tested.
Regarding point 2, Applicant has demonstrated synergy when using the antibody RMP-1-14. There is no objective evidence to establish a trend that any inhibitor across the whole of the genus would produce similar synergy. Moreover, if only one PD-1 inhibitor has been tested, there is insufficient objective evidence to conclude that this unexpected property of combining the checkpoint inhibitor with CXCL is generalizable to inhibiting other targets, such as PD1-L2. L1 and L2 represent two distinct receptors for PD1 and there is insufficient evidence provided regarding whether RMP-1-14 in the examples inhibits both equally and, if so, whether the synergy demonstrated is attributable to inhibiting both such that synergy would not be seen if only inhibiting one of the two receptors.
Regarding point 3, claim 1 covers the use of any cell—mammalian, plant, fungal, bacterial—to deliver the polynucleotide. As stated in the specification at paragraph 42, the CXCL chemokines are naturally secreted by CD103+ dendritic cells. This same paragraph suggests that using APCs are important to “overcome the immunosuppressive tumor microenvironment”. Only DCs are supported by objective evidence, which is insufficient to establish a trend that all APCs or even all cells would result in the same synergy. Rather, if the APC is important to delivery as suggested by the specification, it is possible that cells other than APCs or even other than specifically DCs would not overcome this hurdle and fail to demonstrate synergy. This is supported by Spranger (previously cited) which states that CD103+ DCs are “required for the recruitment of effector T cells into the TMA and are a major component of the establishment of the T cell-inflamed tumor phenotype” (p.720 C2). While other cells might be therapeutic, the evidence of record suggests the important of CD103+DCs which reasonably contribute to the demonstrated synergy over other choices.
Regarding point 4, the objective evidence supports direct injection of the cells into the tumor. This does not provide objective evidence to the person of ordinary skill in the art to generalize this synergy to administering the cells via other routes such as intravenous, intranasal, intraperitoneal, etc. (paragraph 105 of the specification). While these routes might result in the expected therapeutic result, there is a lack of evidence to predict a synergistic result thereby requiring undue experimentation on the part of others to determine which routes preserve the unexpected synergy.
It is possible that the synergy is attributable to the choice of a specific PD-1 inhibitor and that variables such as the timing or delivery method would not affect this synergy.
It is possible that the synergy is attributable to the simultaneous delivery of the checkpoint inhibitor and the CXCL polynucleotide and that variables such as the specific anti-PD-1 or delivery method would not affect this synergy.
It is possible that the synergy is attributable to the choice of delivering the polynucleotide using a dendritic cell and that variables such as the timing or checkpoint inhibitor would not affect this synergy.
It is possible that the synergy is attributable to the intratumoral delivery of the cells and that variables such as the timing or inhibitor would not affect this synergy.
It is possible that the synergy is attributable to the combination of two or more of the variables used in the examples and that there is no generalizable trend of synergy when deviating from those examples.
These are just a few of the possibilities. After reading the specification and considering the record as a whole, Applicant has failed to provide sufficient objective evidence “to determine a trend in the exemplified data”. The specific, narrow embodiment of the disclosed examples lacks sufficient evidence to generalize the claimed synergy across the whole of the genus now claimed. Thus, it is left to others to determine if any other combination results in the claimed synergy and, if so, which variables are important and which are not. This is undue experimentation.
See the decision in Rasmusson v. SmithKline 413 F.3d 1318, 1325 (Fed. Cir. 2005) which stated:
“Thus, at the end of the day, the specification, even read in the light of the knowledge of those skilled in the art, does no more than state a hypothesis and propose testing to determine the accuracy of that hypothesis. That is not sufficient. [Citation omitted.] ‘If mere plausibility were the test for enablement under §112, applicants could obtain patent rights to “inventions” consisting of little more than respectable guesses as to the likelihood of their success. When one of the guesses later proved true, the “inventor” would be rewarded the spoils instead of the party who demonstrated that the method actually worked.’”
It is Applicant’s hypothesis that any cell comprising the claimed polynucleotide(s), delivered in any way, in combination with any immune checkpoint inhibitor, where the two are delivered to the same patient separated by any amount of time, will produce the synergistic effects demonstrated in the specification by a particular embodiment within that genus; see claim 1. However, since synergy is unpredictable and Applicant themselves characterizes the synergy as “unexpected”, there is no basis for concluding that this embodiment generalizes across the scope of the claims. While plausible, the actual testing and determination of the accuracy of Applicant’s hypothesis is left to others, which does not meet the requirements for enablement.
Therefore, claims 1-3, 5, 9-10, 14, 17-18, 23-24, 32-33, and 41 are not enabled for their full scope.
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.
Claim 23 is 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.
Claim 23 recites the limitation "the CXCL9 polypeptide" in line 1 among other such recitations. Claim 1 was amended to remove the polypeptides and polynucleotide options, leaving only the cell option. Claim 23 has not been similarly amended and now references limitations that are no longer present. This broadens the claim (e.g., by allowing administration of “the CXCL9 polypeptide” directly), which does not comply with §112(d).
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 § 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.
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) 1-3, 5, 9-10, 14, 17-18 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Spranger (previously cited) in view of Beech (US20160089398; previously cited) and further in view of Dubinett (US 20180194825; previously cited).
Spranger teaches dendritic cells (DCs) produce CXCL9 and CXCL10 (abstract). Spranger also teaches that T cells are effective to recognize and kill cancer cells but that lack of both CXCL9 and CXCL10 leads to a failure to recruit effector T cells into tumors (abstract). Spranger concludes that the lack of DCs leads to immune escape of tumors. Spranger states that DCs—producing CXCL9 and CXCL10—are necessary for T cell recruitment to tumors and by extension necessary for the anti-cancer effectiveness of T cells (p.720 C2). Spranger also teaches that increased T cell infiltration correlates to checkpoint blockade immunotherapy (p.720 C2), where this increased infiltration is also correlated to the expression of CXCL9 and CXCL10 (p.720-721). Spranger does not teach genetically modifying DCs to express these polypeptides.
Given the importance of CXCL9 and CXCL10 in DCs to the effectiveness of treating cancer by DCs, one of ordinary skill in the art at the time of filing would have been motivated to genetically engineer DCs to promote expression of these important polypeptides. Beech teaches a method for genetically engineering cells to produce specific polypeptides. Beech teaches a vector which allows a cell to produce IL-12 and PD-L1 (claim 1). This lentiviral vector (claim 3) is introduced into a human dendritic cell (claims 8 and 9). These cells are administered to treat tumors (claim 22), IL-12 being known to contribute to the protective immune response, suppression of tumorigenesis (paragraph 6), and supportive activity on T cells (paragraph 7).
Thus, at the time of filing, it would have been obvious to substitute the IL-12 polynucleotide with a combination of CXCL9 and CXCL10 polynucleotides, which meets the limitations of a cell (dendritic cell) comprising CXCL9 and CXCL10 polynucleotides. Both IL-12 and CXCL9/10 are involved in anti-cancer therapy and support T cell anticancer effects. Further, one would choose dendritic cells because Spranger teaches the importance of CXCL9/10 to the effectiveness of this cell type. One would have had a reasonable expectation of success because dendritic cells are amenable to genetic inclusion of a polynucleotide vector which expresses an anticancer, T cell supporting polypeptide (Beech) and Spranger teaches the DCs express CXCL9/10, indicating that expression of these polypeptides by the cell would be expected to achieve similar results.
This combination does not explicitly suggest including an immune checkpoint inhibitor. Dubinett is also concerned with treating cancer (claim 1). Dubinett teaches administering a dendritic cell (claim 12) which comprises a vector (claims 11 and 8), wherein the vector comprises a polynucleotide encoding a tumor inhibitor (claim 1; abstract). Dubinett also teaches this dendritic cell is administered in combination with a checkpoint inhibitor (abstract; claim 1).
Thus, at the time of filing, it would have been obvious to include administration of a checkpoint inhibitor in the method of Spranger/Beech, arriving at the instant method of claim 1. Spranger/Beech makes obvious administering a dendritic cell encoding CXCL9/10 to treat cancer. Dubinett also administers vector-containing DCs to treat cancer and teaches they are effective when combined with a checkpoint inhibitor, suggesting the inclusion of said checkpoint inhibitor in the anti-cancer treatment. Further, Spranger notes that the T cell activation—supported by the DCs as described above—is correlated to checkpoint blockade effectiveness (see above), providing further motivation to include such treatment. The combination of these references would have made instant claim 1 obvious at the time of filing.
With respect to the claim limitation “the combination of said administrations exhibits synergistic anti-tumor effects”, it is recognized that the art lacks the actual combination of the claimed elements. However, Spranger teaches that by using CD103+ DCs, the cells “restore…clinical activity of checkpoint blockade and other immunotherapies in non-T cell-inflamed tumors” (p.720 C2). Thus, while checkpoint therapy was known to have some therapeutic effects as discussed above, Spranger teaches that this checkpoint therapy is less effective without DC recruitment. The person of ordinary skill therefore knew that 1) DCs expressing CXCL9 and CXCL10 were therapeutic for tumors, 2) checkpoint inhibitors were therapeutic for tumors, and 3) checkpoint inhibitors alone are not functioning with maximum activity in the absence of DC recruitment. The person of ordinary skill in the art would have expected a degree of synergy when combining these therapies because not only are the DCs therapeutic but the DCs also restore some of the therapeutic efficacy of checkpoint inhibitors.
Regarding claims 2, 3, and 5, Dubinett teaches the checkpoint inhibitor is Pembrolizumab (claim 5; paragraph 22). Pembrolizumab is recited by instant claim 5, is a PD-1 inhibitor recited by instant claim 3 (see Dubinett paragraph 22), and is a monoclonal antibody recited by instant claim 2 (see Dubinett paragraph 145). As it would have been obvious to include a checkpoint inhibitor given the teachings above, including Dubinett, it would have been obvious to select an effective checkpoint inhibitor taught by Dubinett, including Pembrolizumab.
Regarding claim 9, introducing a polynucleotide encoding CXCL9/10 into a vector and in turn introducing that vector into a DC would have been obvious as above. Further, Dubinett teaches administration intratumorally (paragraphs 164, 173; claim 16). Beech also teaches intratumoral administration (claim 22; paragraph 9). It would have been obvious to select a route known in the art, such as the preferred intratumoral route of both Beech and Dubinett, which meets the limitations of “to the tumor site”. As the combination is an anti-cancer therapeutic, it would have further been obvious to administer it to the subject which has the tumor in order to treat the tumor, meeting the limitations of “to the subject”.
Regarding claim 10, Beech claims the polynucleotide introduced into a lentiviral vector (claim 3), rendering such a choice obvious.
Regarding claim 14, Beech teaches the dendritic cells may be autologous (paragraph 455) as does Dubinett (claim 13), making the choice of autologous DCs obvious.
Regarding claim 17, intratumoral administration is addressed above. Further, Beech teaches the method as applied to treat a solid tumor (paragraph 545) as does Dubinett (paragraph 16).
Regarding claim 18, Dubinett teaches the combination cancer treatment is effective to treat NSCLC (paragraph 30), rending it obvious to administer the known effective checkpoint inhibitor in combination with the dendritic cell (Dubinett) enhanced with the CXCL9/10 vector with a reasonable expectation of success as this treatment is taught as effective and the genetic modification is expected to increase the efficacy of the cells for reasons above. Beech also teaches the treatment for NSCLC (paragraph 454).
Regarding claim 23, administration intratumorally is addressed above. Further, Dubinett, which teaches the combination of DC and checkpoint inhibitor therapy, teaches specifically the cells (DCs) are administered intratumorally (claim 16). Dubinett exemplifies one method of administration where the checkpoint inhibitor is administered intravenously while the cells are administered intratumorally (paragraph 174). This would have made obvious such dosing routes at the time of filing.
Therefore, claims 1-3, 5, 9-10, 14, 17-18 and 23 would have been obvious.
Claim(s) 24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Spranger/Beech/Dubinett as applied to claims 1-3, 5, 9-10, 14, 17-18 and 23 above, and further in view of Chabanon (previously cited).
The discussion of Spranger/Beech/Dubinett is set forth above and incorporated herein. This combination does not explicitly describe the subjects as having an increased mutational burden.
Chabanon teaches that immune checkpoint therapy is not a universal treatment (abstract). Chabanon suggests using “mutational load and neoantigens” for clinical implementation (abstract). Chabanon teaches there is no clear threshold for “high” or “low” and that subjects with both high mutational burden as well as “very low” burden at all may still respond to immune checkpoint treatment (p.4311 C2). Chabanon also teaches tumor-specific antigens (i.e., neoantigens) generally associate with clinical efficacy of immune blockade (p.4311 C2).
Regarding claims 24 and 33, at the time of filing, it would have been obvious to administer the cancer treatment of Spranger/Beech/Dubinett to subjects with increased mutational burden because Chabanon teaches that mutational burden is not indicative of the efficacy of immune checkpoint inhibitors nor does Chabanon provide any reasoning why these would be indicative of treatment with the DCs. Moreover, the groups of “very low” or “virtually no mutation” still meets the criteria for an “increased mutational burden tumor” when compared to a tumor with zero mutations; “virtually no mutation” still requires at least one mutation. Thus, one of ordinary skill in the art would have been motivated to administer this therapy to this population as the DC treatment would have had a reasonable expectation of success and the art teaches the DCs improve the efficacy of checkpoint inhibitors, so would have included such treatment.
Therefore, claim 24 would have been obvious.
Claim(s) 24, 32-33, and 41 is/are rejected under 35 U.S.C. 103 as being unpatentable over Spranger/Beech/Dubinett as applied to claims 1-3, 5, 9-10, 14, 17-18 and 23 above, and further in view of Bhagavatheeswaran (CA3058175; form 892).
The discussion of Spranger/Beech/Dubinett is set forth above and incorporated herein. This combination does not explicitly describe the subjects as having an increased mutational burden nor one of the claimed assays for detecting the mutational burden.
Bhagavatheeswaran is also concerned with administering checkpoint inhibitors, specifically PD-1 inhibitors, to treat cancer (claim 1). Bhagavatheeswaran teaches selecting a subject with a high mutational burden as measured by, e.g., FOUNDATIONONE® (claims 1 and 6).
Regarding claim 24, it would have been obvious to one of ordinary skill in the art at the time of filing to administer the combined therapy to a subject with a high (increased) mutational burden because Bhagavatheeswaran teaches these subjects are amenable to checkpoint inhibitor therapy and the combination of references suggests the improved efficacy of including the CD103+ DCs expressing CDCX9/10.
Regarding claim 33, Bhagavatheeswaran teaches assaying for mutations in KRAS (paragraph 199) and that mutations in KRAS drive are associated with lower (but still increased above zero) mutational burden (paragraph 161). The person of ordinary skill in the art would therefore have known that mutations is KRAS are associated with tumors and subject to treatment, which would have made it obvious to treat said tumros.
Regarding claims 32 and 41, it would have been obvious to use a known method of measuring this burden and so it would have been obvious to select one of the known methods disclosed in Bhagavatheeswaran, such as FOUNDTATIONONE®. Note that, as discussed above in the §112b rejection, a trademark identifies the source of a product and not the product itself. However, as no specifics of the product are instantly claimed nor disclosed in the instant specification, the disclosure of the same tradename assay being used for the same purpose is considered sufficient to determine that the Bhagavatheeswaran assay meets the limitations of the instant assay.
Therefore, claims 24, 32-33, and 41 would have been obvious.
Response to Arguments
Applicant's arguments filed 4/22/26 have been fully considered but they are not persuasive.
Regarding the specification, Applicant states that the generic terminology is “provided or implied”. However, the specification has not “provided” the generic terminology in, e.g., paragraphs 89 or 93 because there is no language other than the trademarks/tradenames which would indicate what a generic form of, for example, “Foundationone CDxtm” requires. Further, there is no provision in the MPEP for generic terminology being “implied” when using a tradename. As noted in the previous “Specification” section and reiterated in the §112b rejection above, a tradename indicates a source of goods and does not imply anything about the product itself. To use a trademark to identify a particular product not only renders a claim indefinite but also constitutes an improper use of the trademark (MPEP §2173.05(u)). If the trademark is not meant to define a limitation but rather lead one to an implied product or assay, then the trademark should be removed from the claim because the presence of language in a claim that is not meant as a limitation creates confusion as the purpose of a claim is to set forth the limitations of protection being sought.
Regarding the arguments against the enablement rejection, these were persuasive. However, none of these arguments apply to the new enablement rejection necessitated by the amendments.
Regarding the rejection under §103, Applicant argues that “administration of cells expressing CXCL9/10 and an immune checkpoint inhibitor provides an unexpectedly better outcome in anti-tumor effects than the additive combination” (remarks 4/22/26 p.9). Applicant points to figures 5B and 8 in support of this.
This has been fully considered but is not persuasive. Applicant’s data in 5B and 8 are not commensurate in scope with what has been claimed. While Applicant asserts the unexpected results for “an immune checkpoint inhibitor”, only one specific inhibitor is used in these experiments. This is not representative of all PD-1 inhibitors nor of any PD1-L1 or PD1-L2 inhibitors as claimed. As discussed in the enablement rejection, a PD-1 inhibitor may inhibit the interaction of PD-1 with one or both of the receptors, which does not inform the artisan of the expected result when only inhibiting one receptor. The synergy may arise from inhibiting both receptors by way of inhibiting PD-1, in which case inhibiting only one or the other receptor would not achieve the same synergy. The PD-1 inhibitor used may only inhibit, e.g., the PD1/L1 interaction, in which case an L2 inhibitor would not achieve the same synergy.
Further, as necessitated by amendment, the rejection now articulates evidence which suggests the synergy of the combination would have been expected rather than unexpected. The evidence offered in the specification shows a greater than additive effect. As stated by MPEP §716.02(a), while a greater than additive effect is probative of the question, this alone is insufficient to establish non-obviousness because that effect may be expected. Further, it is Applicant’s burden to establish that the differences are in fact unexpected (MPEP §716.02(b)). Applicant has pointed to the synergy presented in the specification but does not elaborate on why this was unexpected. In contrast, the art provides a reason to expect this; briefly, that the DC administration restores a degree of efficacy to the checkpoint inhibitors that is absent with the checkpoint inhibitor alone.
It is recognized that both a prior art rejection and scope of enablement rejection is now of record. However, it is this lack of adequate evidence which requires both. In one case, Applicant is correct that the combinations are unpredictable and result in an unexpectedly greater benefit, in which case the broad scope being claimed is not enabled. In another, the art’s suggestion of DCs improving checkpoint inhibitor is evidence that the claimed synergy was expected, in which case the claims may be enabled beyond the specific scope articulated but also obvious. Without sufficient evidence to determine which scenario is correct, both rejections are made of record in accordance with the requirements of compact prosecution.
Applicant argues Dubinett does not provide evidence of synergy because Dubinett engineers the cells to express a different inhibitor. This is not persuasive because Dubinett does not need to provide this expectation alone. Dubinett does teach combining DCs with checkpoint inhibitors while Spranger also provides a suggestion that this combination would have been expected to be better than the additive effects of either alone.
Applicant’s elected species have not been deemed allowable and so Applicant’s argument for the inclusion of examination of claims 6 and 11 is not persuasive. The Examiner does, however, confirm that upon the allowance of an elected species, additional species will be examined until either one additional species is rejected or all pending claimed species are determined to be allowable. This would include extension of examination to claims 6 and 11 if appropriate. See MPEP §803.02(III)(C)(2) for additional guidance.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Adam Weidner/Primary Examiner, Art Unit 1675
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