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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 64-83) and the following species “a loss of expression”, specifically a loss of CD58 expression, in the reply filed on 9 April 2026 is acknowledged. While Applicant asserts that claims 64-83 read upon the elected species this is not the case. Applicant has elected loss of expression, which means the alternative of “one or more molecular alterations in CD58 activity” is not elected. Thus, claim 70-74 and 83, all pertain to the one or more alterations, are withdrawn (see Restriction requirement pg. 4 bullet (A)).
Claims 70-74 and 83-86 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim.
Claims 64-69 and 75-82 read upon the elected species and are examined upon their merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is the national stage entry of PCT/US2021/058102 filed on 4 November 2021 , which claims priority to U.S. Provisional Patent Application Serial No. 63/109,611, filed on November 4, 2020.
Claims 64-69 and 75-82 have an effective US filing date of November 4, 2020.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 7 May 2024 and 5 November 2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are considered by the examiner.
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 64-69 and 75-82 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.
The term “increased unresponsiveness” in claim line 2 of Claim 64 is a relative term which renders the claim indefinite. The term is neither defined by the claim, nor does the specification provide a standard for ascertaining the requisite degree of increased unresponsiveness. Thus, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim 64 is further indefinite wherein it recites “optimizing the therapeutic efficacy” without reciting any positive, active method steps for “optimizing”. A person having ordinary skill would not know what is encompassed by “optimizing”. Thus, it is unclear what is required for direct infringement of the method.
Claim 64 is further indefinite wherein it recites an expression level of CD58 is decreased “or lost” (part a line 2; part b(i) line 3; b(ii) line 3 and part b(v) line 2). It is unclear what is meant by expression is “lost” or how a person would know when expression lost since there is no assessment of previous expression levels. While decreases relative to a reference expression level is clear, determining whether or not expression is “lost” also requires a standard as well, and that standard is missing from the claim itself. Therefore, the metes and bounds of the claims are indefinite.
These rejections affect the scope of all claims that depend from Claim 64.
Claim 66 is indefinite wherein it recites “further comprising treating the health condition.” The claim recites no steps whereby “treating” is achieved. A person having ordinary skill in the art would not know what method steps are encompassed by the term “treating”. Nor is it clear whether or not an assessment of beneficial treatment is required for direct infringement of the method.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 64-69 and 75-82 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. The claim(s) recite(s) “determining the responsiveness of an individual” which is a natural phenomenon in itself; and further recite “identifying the individual who has increased unresponsiveness”, “optimizing” therapy, “selecting the individual”, and “identifying a therapeutically effective amount…”, which are mental step processes. These judicial exceptions are not integrated into a practical application because the steps/elements in addition to these judicial exceptions do not present any of the considerations under MPEP 2106.05(a-c), (e) and (h). The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional steps/elements recite nothing more than what was well-understood, routine, and conventional at the time of filing.
The claim is directed to a method, which is one of the statutory categories of invention (STEP 1:YES).
As stated above the claims recite more than one judicial exception. The claims recite determining the responsiveness of an individual to a CAR-T cell therapy, and one’s innate responsiveness is a natural phenomenon. Claims further recite: “identifying” an individual who has an increased unresponsiveness to a CAR- T cell therapy, “optimizing” the therapeutic efficacy of a CAR-T cell therapy in an individual, and administering a CAR-T cell therapy to an individual and comprise the steps of a) “detecting” whether an expression level of CD58 is decreased compared to a reference expression level of CD58 or lost or one or more molecular alterations in CD58 activity is present in a biological sample obtained from the individual, wherein said detecting comprises contacting the biological sample with a detection reagent and detecting an interaction between the detection reagent with a CD58 encoding gene or a product thereof in the sample; and b) (i) “identifying” the individual as having decreased responsiveness to treatment with the CAR-T cell therapy if the expression level of CD58 is decreased compared to a reference expression level of CD58 or lost or at least one of the one or more molecular alterations in CD58 activity is detected in the sample,(ii) “selecting” the individual as having increased unresponsiveness to treatment with a CAR-T cell therapy if the expression level of CD58 is decreased compared to a reference expression level of CD58 or lost or at least one of the one or more molecular alterations in CD58 activity is detected in the sample; or (iii) “identifying” a therapeutically effective amount of the CAR-T cell therapy based on the detected interaction between the detection reagent with the CD58 encoding gene or a product thereof; or (iv) administering a therapeutically effective amount of the CAR-T cell therapy based on the detected interaction between the detection reagent with the CD58 encoding gene or a product thereof; or (v) administering a treatment with a CAR construct comprising a CD2 signaling domain to the individual based on the detection of a decreased or lost expression level of CD58 or one or more molecular alterations in the CD58-encoding gene in step (a). Determining, detecting, optimizing, identifying and selecting are all mental processes that are encompassed under the enumerated group (c) of the Abstract Ideas set forth in MPEP 2106.04(a)(2)(III) which states: “Mental processes — concepts performed in the human mind (including an observation, evaluation, judgment, opinion). These mental processes of the claims are analogous to claims the courts have said recite mental processes:
• a claim to "collecting information, analyzing it, and displaying certain results of the collection and analysis," where the data analysis steps are recited at a high level of generality such that they could practically be performed in the human mind, Electric Power Group v. Alstom, S.A., 830 F.3d 1350, 1353-54, 119 USPQ2d 1739, 1741-42 (Fed. Cir. 2016);
• claims to "comparing BRCA sequences and determining the existence of alterations," where the claims cover any way of comparing BRCA sequences such that the comparison steps can practically be performed in the human mind, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 763, 113 USPQ2d 1241, 1246 (Fed. Cir. 2014);
• a claim to collecting and comparing known information (claim 1), which are steps that can be practically performed in the human mind, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1067, 100 USPQ2d 1492, 1500 (Fed. Cir. 2011); and
• a claim to identifying head shape and applying hair designs, which is a process that can be practically performed in the human mind, In re Brown, 645 Fed. App'x 1014, 1016-17 (Fed. Cir. 2016) (non-precedential).
Therefore the claims recite at least one judicial exception (STEP 2A, Prong One: YES).
According to Step 2A, Prong Two, MPEP 2106.04(d), the claims are next evaluated with respect to whether the judicial exception is integrated into a practical application. This analysis turns to the additional elements recited within the claim, are:
detecting whether an expression level of CD58 is decreased compared to a reference expression level of CD58 or lost or one or more molecular alterations in CD58 activity is present in a biological sample obtained from the individual, wherein said detecting comprises contacting the biological sample with a detection reagent and detecting an interaction between the detection reagent with a CD58 encoding gene or a product thereof in the sample;
and, administering a therapeutically effective amount of the CAR-T cell therapy based on the detected interaction between the detection reagent with the CD58 encoding gene or a product thereof; or (v) administering a treatment with a CAR construct comprising a CD2 signaling domain to the individual based on the detection of a decreased or lost expression level of CD58 or one or more molecular alterations in the CD58-encoding gene in step (a).
These additional steps do not reflect any improvement within the technical field because they constitute no novel means for detecting or administering. The claims recite no particular machine; nor do they effect a transformation. In general, there are no additional elements that apply the judicial exception in some other meaningful way beyond generally linking it to a field, namely, CAR-T cell therapy. While the second additional step is directed to administering a therapeutically effective amount based on an interaction with a detecting reagent and the CD58 encoding gene or a product thereof or administering a treatment with a CAR construct comprising a CD2 signaling domain to the individual based on the detection of a decreased or lost expression level of CD58. MPEP 2106.04(d)(2) states that in order to qualify as a ‘treatment’ or ‘prophylaxis’ limitation for purposes of the particular treatment or prophylaxis in Step 2A Prong Two, the claim limitation in question must affirmatively recite an action that effects a particular treatment or prophylaxis for a disease or medical condition. In the instant claims, treatment is conditional upon the detection of CD58 because the claims administer a therapeutically effective amount of the CAR-T cell therapy based on the detected interaction between the detection reagent with the CD58 encoding gene or a product thereof. This is so generic as to not be particular to the application of the judicial exception in any way. Therefore, the claims, as a whole, amount to nothing more than a drafting effort designed to monopolize the natural correlation itself and, regarding the mental process judicial exceptions, append the words “apply it” to the field of CAR-T therapy. ((STEP 2A, Prong Two: NO).
Regarding the method claimed, the specification states no new technology but rather cites “PCR-based analytical assays known in the art are suitable for the methods disclosed herein” (pg. 27); “DNA probes that can be designed and prepared using methods and techniques known to those having ordinary skill in the art” and “Other variations of the FISH method known in the art are also suitable for evaluating an individual selected in accordance with the methods disclosed herein” (pg. 28); “The value of the dissociation constant can be determined directly by well-known methods”, “The binding kinetics and binding affinity of the polypeptide to its ligand also can be assessed by standard assays known in the art” (pg. 29); “a ‘therapeutically effective amount’ will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques” (pg. 31). Therefore, in accordance with Berkheimer Memo III.A.1, the examiner has cited express statements in the specification indicates that the additional elements are sufficiently well-known that the specification does not need to describe the particulars thereof. In other words, the disclosure describes no new technology, but merely refers to techniques and elements that were known in the art at the time of filing.
Lastly, in accordance with Berkheimer Memo III.A.III. the examiner cites publications within the field of technical expertise, that demonstrate the well-understood, routine, conventional nature of the additional element(s). The following prior art teaches it was well established in the field of technical expertise that loss of CD58 was a well-understood feature of tumors that have unfavorable prognostic factors (Cao et al., Oncotarget, Vol.7, No, 50: 83294-83307, 2016). Even Applicant’s own post-filing date reference teaches, “CD58 mutations have been reported in many cancers, including multiple myeloma and colon cancer” (Majzner et al., Blood 136 (Suppl 1): 53-54, 4 November 2020). Therefore, the detection steps/elements recited in addition to the judicial exception was well-understood, routine, conventional activities in the field of cancer. Additionally, it was well established that “low CD2 impairs CD8+ TILs and hence increasing CD2 expression provides an attractive angle to improve TIL function” (Demetriou et al., Nature Immunology, 21(10): 1232–1243, 10 July 2021). Demetriou and colleagues conclude, “Engineering T cells to bolster CD2 expression might make them more resilient in adoptive immunotherapy of solid tumors” (last line). The use of CD2 signaling in second-generation chimeric antigen receptors was well-understood prior to the filing date of the instant application (see US Patent 9783591 B2, issued 10 October 2017). Therefore, the claimed steps/elements recited in addition to the judicial exception(s), alone or in combination, do not make an inventive contribution over the methods that were known in the art prior to filing, (STEP 2B: NO).
For all of these reasons, Claims 64-69 and 75-82 are directed to the judicial exception without significantly more and are rejected.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
Claims 64-69, 75-78 and 81 are rejected under 35 U.S.C. 103 as being unpatentable over Cao et al., Oncotarget, Vol.7, No, 50: 83294-83307, 2016; in view of Rosskopf et al., Oncotarget, Vol. 9, No. 25: 17608-17619, 2018.
Regarding claim 64, Cao et al. teach methods comprising detecting whether an expression level of CD58 is decreased compared to a reference expression level of CD58 or lost or one or more molecular alterations in CD58 activity is present in a biological sample obtained from the individual. Specifically, Cao et al. teach copy number loss of CD58 (abstract) and mutations in CD58 (pg. 83298, second column) are both associated with poor prognosis in Diffuse large B-cell lymphoma (DLBCL). Cases with CD58 mutation, 80% exhibited negative protein expression, and one sample showed loss of CD58 surface protein expression (Supplementary Figure S4A). Patients lacking CD58 protein expression had significantly shorter progression-free survival (PFS) than those with CD58 expression (Supplementary Figure S4B). These studies were performed on genomic DNA extracted from formalin-fixed paraffin-embedded (FFPE) diagnostic biopsies (pg. 83304, Materials and Methods, first two paragraphs). For the detection of somatic mutations, a custom Ion AmpliSeq panel was designed to target 27 candidate genes, including CD58 coupled to Ion Sphere particles and detected with the Ion OneTouch system (pg. 83305, first paragraph). Therefore, the prior art teaches detecting comprising contacting the biological sample with a detection reagent and detecting an interaction between the detection reagent with a CD58 encoding gene in the sample.
Regarding claim 65, Cao et al. teach the individual has a health condition associated with (i) a decreased level or loss of CD58 expression compared to a reference expression level of CD58 or (ii) with one or more molecular alterations in CD58 activity, specifically, Diffuse large B-cell lymphoma (DLBCL) cancer (Abstract).
Regarding claim 66, the Cao et al. reference further teaches treating the health condition, wherein it discloses the clinical success of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DAEPOCH) over R-CHOP in treating patients with MYC+DLBCL has highlighted the profound impact of molecular aberrations on clinical management for an improved clinical outcome (pg. 83295, first paragraph).
Regarding claim 67, the DLBCL of the Cao et al. reference teaches the hematological malignancy of the instant claim.
Regarding claims 68 and 69, Cao et al. disclose one or more molecular alterations in CD58, namely, mutations and copy number losses of the CD58 gene in diffuse large B cell lymphoma are independent unfavorable prognostic factors (Abstract). This teaches the specific loss of expression and mutated form of CD58, both of which are recited in instant claim 69.
Regarding claim 81, this teaches the antigen, namely CD58, is decreased in the tumor cells compared to wildtype cells.
While the Cao et al. prior art does not expressly teach identifying the individual as having decreased responsiveness to treatment; or, selecting the individual as having increased unresponsiveness to treatment with a CAR-T cell therapy, as stated above, these limitations are mental processes and are judicially created exceptions to subject matter eligibility. Therefore, these cannot be what distinguishes the claimed invention over the methods of the prior art. Furthermore, mental processes are not typically disclosed in prior art references.
Lastly, the Cao et al. prior art fails to disclose administering a treatment with a CAR construct comprising a CD2 signaling domain to the individual (as recited in instant claim 64). Nor does Cao et al. teach administering a CAR-T cell therapy to the individua as single therapy or in combination with one or more additional therapies (instant claim 75); wherein the CAR-T cell therapy targets an antigen expressed by a cancer cell (instant claim 76); wherein the cancer is a B-cell malignancy (instant claim 77); wherein the CAR-T cell therapy targeting the antigen expressed by the B-cell malignancy comprises a CAR construct comprising a CD2 signaling domain (instant claim 78).
Rosskopf et al. prior art references, however, remedy this deficiency. Rosskopf et al. teach cancer cells often express CD58, the ligand for CD2, and CD112 and CD155, which function as ligands for CD226 (pg. 17610, second column and Supplementary Figure 1A). When CD58 is expressed on the tumor cells, a chimeric receptor comprising a CD2 signaling domain can bind, but otherwise CARs that do not comprise CD2 domains, such as CD226::CD28 or TIGIT::CD28, are more effective since CD155 is expressed fairly ubiquitously (Figure 4A). Rosskopf et al. state, “we have adopted this strategy and devised chimeric receptors where CD28 signaling domains were fused to the extracellular binding domains of either CD2, CD226 or TIGIT and thus can be engaged by CD58 or CD155 expressed on the tumor targets” (pg. 17612, section titled ‘Chimeric CD28 receptors boost sensitivity to antigen’).
It would have been obvious to a person having ordinary skill in the art, before the effective filing date of the application, to administer a CD2-comprising CAR construct when CD58 is expressed on the cancer cells since CD58 and CD2 are binding partners, as taught by the Rosskopf et al. prior art, but to use alternative CARs that do not comprise CD2, such as CD226::CD28 or TIGIT::CD28, when CD58 is not expressed for the CAR comprising a CD2 signalling domain to interact with. And it is obvious to a person having ordinary skill in the art that one would have to use the method of Cao et al. to detect CD58 expression in tumor biopsy samples in order to select a CAR T therapy. In KSR International Co. v. Teleflex, Inc., the Supreme Court has stated that where there is a “pressure to solve a problem and a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense” (KSR International Co. v. Teleflex, Inc. 127 S. Ct. 1727, 82 USPQ2d 1385, Supreme Court, April 30, 2007). In the instant case, the problem to be solved is which CAR-T cell therapy to administer for the effective treatment of cancer. The art demonstrates that there are a finite number of identified tumor antigens to be targeted by these CAR constructs – namely CD80, CD58 and CD155 (Figure 4A Rosskopf et al.) - and a finite number of CAR signalling domains that can target these antigens: CD226::CD28 or TIGIT::CD28 for targeting CD155 on the tumor cells, OR CD58-CD2::CD28 if CD58 is present on the tumor cells. It was well within the technical grasp person of having ordinary skill in Oncology to pursue any one of these known options with predictable success since each of these constructs demonstrated success in the prior art. Thus, the method of the invention is likely the product not of innovation but of ordinary skill and common sense.
Therefore, the invention of Claims 64-69, 75-78 and 81 is rendered obvious by the teachings of the prior art references.
Conclusion
Claims 64-69 and 75-82.
While they have been rejected above it should be noted that there was nothing within the prior art that taught or suggested the method of the claims further comprising wherein the antigen expressed by the B-cell malignancy is CD-19 and the CAR construct comprising a CD2 signaling domain further comprises an anti-CD 19 scFv domain with the amino acid sequence of SEQ ID NO: 4 (the limitations of instant claims 79-80 and 82). SEQ ID NO: 4 is equivalent to anti-FMC63 scFv 28Z synthetic receptor construct see first hit on attached pBLAST search results.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STACEY NEE MACFARLANE whose telephone number is (571)270-3057. The examiner can normally be reached M-F 7:30-5 (EST) & Sat. A.M..
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/STACEY N MACFARLANE/Examiner, Art Unit 1675
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