DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .2. The examiner reviewing your application at the PTO has changed. Please address future correspondence regarding this application to examiner Carla Myers.
Election/Restrictions
3. Applicant’s election without traverse of Group II and the species of cancer immunotherapy, a missense mutation and particularly the R260H missense mutation listed in Tables 1-3 and 6, and the cancer of “colon adenocarcinoma (CRC)” in the reply filed on 28 May 2026 is acknowledged.
Upon further consideration, Group I has been rejoined with Group II.
Claim Status
4. Claims 12, 13, 17, 25, 31, 32, 37, 38, 42, 49, 50, 56, 63, 65, 83 and 133-137 are pending.
Claims 32, 37, and 65 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.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 12, 13, 17, 25, 31, 38, 42, 49, 50, 56, 63, 83 and 133-137 read on the elected invention and have been examined herein. It is noted that claim 25 encompasses non-elected species of anti-cancer therapies other than the elected species of cancer immunotherapy; claims 31 and 42 encompass non-elected species of mutations other than the elected R260H mutation; and claim 63 encompasses non-elected species of cancer, other than the elected species of CRC. Prior to the allowance of claims, any non-elected subject matter which has not been rejoined with the elected subject matter will be required to be removed from the claims.
Specification
5. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code – see, for example, para [0267], [0573], and [0576]. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code, such as “www.”. See MPEP § 608.01.
Improper Markush Grouping Rejection
6. Claims 31 and 42 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush groupings of the mutations listed in Tables 1-4 and 6 (claim 31) and Tables 2-4 (claim 42) and combinations thereof are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
It is first noted that MPEP 2117 states that “A Markush claim may be rejected under judicially approved “improper Markush grouping” principles when the claim contains an improper grouping of alternatively useable members. A Markush claim contains an “improper Markush grouping” if either: (1) the members of the Markush group do not share a “single structural similarity” or (2) the members do not share a common use. Supplementary Guidelines at 7166 (citing In re Harnisch, 631 F.2d 716, 721-22, 206 USPQ 300, 305 (CCPA 1980)). “ Members of a Markush group share a “single structural similarity” when they belong to the same recognized physical or chemical class or to the same art-recognized class (prong 1) and the members of a Markush group share a common function or use when they are disclosed in the specification or known in the art to be functionally equivalent (prong 2).
The phrase “significant structural element is shared by all of the alternatives” refers to cases where the compounds share a common chemical structure which occupies a large portion of their structures, or in case the compounds have in common only a small portion of their structures, the commonly shared structure constitutes a structurally distinctive portion in view of existing prior art, and the common structure is essential to the common property or activity.
A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein “there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved” (see MPEP 2117IIA).
Herein, the recited alternative species do not share a single structural similarity, as each mutation has a different chemical structure in that it consists of a different nucleotide alteration that occurs at a different location in the CD274 gene and each mutation is flanked by a unique nucleotide sequence. Note that the identity of a mutation can only be understood in view of the flanking nucleotides in the gene or the flanking amino acids of the encoded protein. Thus, the mutations do not share a single structural similarity. For example, a mutation in the CD274 gene that leads to an amino acid substitution of an A (alanine) to a T (threonine) at amino acid position 18 of the CD274 protein has a different chemical structure as compared to a mutation in the CD274 gene that leads to an amino acid substitution of an A (alanine to a G (glycine) at amino acid position 254 of the encoded CD274 protein. The only structural similarity present is that all of the mutations involve nucleotides present in a CD274 gene. The fact that the mutations comprise nucleotides per se does not support a conclusion that they have a common single structural similarity because the structure of comprising a nucleotide in a CD274 gene is not essential to the common activity of being correlated with responsiveness of a cancer to a cancer therapy, and particularly to an immune checkpoint inhibitor therapy. See, for instance, claim 50 which recites that “the one or more mutations in a CD274 gene result in an immune checkpoint inhibitor resistant cancer.”
Accordingly, while the different mutations are asserted to have the property of being indicative of responsiveness of a cancer to a cancer therapy, they do not share a single structural similarity essential to this activity.
Further, the recited mutations do not belong to a chemical or art-recognized class because there is no expectation from the knowledge in the prior art that all mutations behave in the same manner and can be substituted for one another with the same intended result achieved. There is no evidence of record to establish that it is clear from their very nature that the recited mutations possess the common property of being indicative of responsiveness of a cancer to a cancer therapy.
Following this analysis, the claims are rejected as containing an improper Markush grouping.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112(b) - Indefiniteness
7. 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 25, 42 and 63 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 25, 42 and 63 are indefinite over the recitation of “mutations listed in Tables 1-4 or 6” (claim 25), “mutations listed in Tables 2-4” (claim 42) and “ “cancer listed in Table 5 or Table 6” (claim 56). See MPEP 2173.05(s) which states:
“Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.” Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).”
Herein, the reference to the CGIs of Table 1 renders the claims incomplete. Note also that tables in the specification may be amended and thereby the information therein is not fixed and renders the claims unclear and indefinite.
Claim Rejections - 35 USC § 112 first paragraph – Written Description
8. 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 12, 13, 17, 25, 38, 49, 50, 56, 63, 83 and 133-137 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a Written Description rejection.
In analyzing the claims for compliance with the written description requirement of 35 U.S.C. 112, first paragraph, the written description guidelines note that with regard to genus/species situations, a “Satisfactory disclosure of a “representative number'' depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the species disclosed.”
The claims are drawn to methods that require obtaining information regarding a CD274 mutation in a sample from a subject, or detecting a mutation in a CD274 gene in a sample from a subject, and responsive to the information or detection administering any anti-cancer therapy to a subject.
The claims encompass determining that any mutation in the CD274 gene is present as indicative of the need to treat a subject with any anti-cancer therapy, and particularly with an immunotherapy (elected species and see claim 50: “wherein the one or more mutations in a CD274 gene result in an immune checkpoint inhibitor resistant cancer”).
Claims 38, 136 and 137 further require that the CD274 mutation results in no expression of PD-L1, or low expression of PD-L1 or high expression of PD-L1.
Claim 49 requires that the CD274 mutation reduces the interaction between a PD-L1 polypeptide encoded by the CD274 gene and a PD-1 receptor; and/or reduces the activity of a PD-Li polypeptide encoded by the CD274 gene.
The claims do not define the CD274 mutation in terms of any particular structural properties or any other relevant identifying characteristics. The claims thereby encompass a significantly large genus of CD274 mutations that may be any single or multiple nucleotide substitution, insertion, deletion or any translocation, transversion or rearrangement of the CD274 gene.
The specification in Table 1 discloses missense mutations, truncations, splice site mutations and insertions/deletions in the CD274 gene. However, the table does not indicate which of the mutations are associated with responsiveness to any anti-cancer therapy or to particular cancer therapies, including an immune therapy, or which mutations are correlated with expression levels of PD-L1 protein or with the activity of PD-L1 or the interaction of PD-L1 with a PD-1 receptor.
Table 2 lists CD274 missense mutations, including the elected R260H mutation, and one CD274 splice site mutation, one CD274 truncation mutation, and one CD274 splice site mutation, which are correlated with low PD-L1 protein expression. Table 3 lists CD274 mutations, including the elected R260H mutation, correlated with no PD-L1 protein expression. Table 4 lists CD274 mutations correlated with an increase in PD-L1 protein expression. Table 6 lists the cancers associated with particular CD274 mutations and teaches that the R260H mutation is detected in the following cancers:
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272
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However, the specification does not clearly teach that the CD274 mutations therein are correlated with responsiveness to all types of anti-cancer therapy or even to the elected species of any cancer immunotherapy. Rather, the specification (para [0590]) teaches:
“While most of the non-truncating SV CD274 mutations had low to no tumor cell expression of PD-L1, the expression levels of PD-L1 differed among the various CD274 SV mutation categories. Interestingly, of the eleven R260H cases concurrently tested with PD-L1 IHC, most showed little to no PD-L1 expression, suggesting that patients with R260H mutations might not be treated with ICPI if only tested with PD-L1 IHC. This contrasted with the five E237K cases, where most cases had some PD-L1 expression, suggesting that the E237K has little to no effect on PD-L1 protein expression. Most other variants were only observed in a single sample (with or without concurrent PD-L1 expression data) due the rarity of the mutations.”
Regarding the activity and function of the encoded PD-L1 protein (claims 38, 136 and 137), the specification states “No correlation between the predicted functional status of missense mutations and PD-L1 IHC expression was observed” (para [0592]).
Thus, while the specification teaches many CD274 missense mutations and additional truncating and frameshift mutations, the specification does not teach a representative number of any type of CD274 mutation that is indicative of responsiveness to any anti-cancer therapy or need to treat a patient with any anti-cancer therapy (responsive to information regarding the CD274 mutation), and particular to the elected anti-cancer therapy of cancer immunotherapy, including mutations associated with no PD-L1 expression or an increase or a decrease in PD-L1 protein expression or reduced activity of PD-L1 or interaction of PD-L1 with a PD-1 receptor. This finding is evidenced in part by the teachings of Murugesan et al (20240410016; co-authored by one of the present inventors) which discloses a large number of CD274 rearrangements – i.e., mutations (see Tables 1-3 therein) – that are characterized as being correlated with response to immune checkpoint inhibitor therapy, which rearrangements are not disclosed in the present application. Note that mutations are described as including rearrangements in the present specification (see, e.g., para [0155] and [0159]).
While the Federal Circuit has recognized that “the written description requirement can in some cases be satisfied by functional description,” it has made clear that “such functional description can be sufficient only if there is also a structure-function relationship known to those of ordinary skill in the art.” In re Wallach, 378 F.3d 1330, 1335 (Fed. Cir. 2004); see also, Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 964 (Fed. Cir. 2002) (holding that the written description requirement would be satisfied “if the functional characteristic of preferential binding . . . were coupled with a disclosed correlation between that function and a structure that is sufficiently known or disclosed”); Amgen Inc. v. Sanofi, 782 F.3d 1367, 1378 (Fed. Cir. 2017) (holding that an “adequate written description must contain enough information about the actual makeup of the claimed products”).
Herein, the claims recite a functional description of the claimed genus of mutations but do not identify a correlation between the claimed function of being indicative of / correlated with responsiveness to an anti-cancer therapy and the structure of the CD274 mutations that perform that function.
Further, as noted in Vas-Cath Inc. v. Mahurkar (19 USPQ2d 1111, CAFC 1991), the Federal Circuit concluded that:
"...applicant must also convey, with reasonable clarity to those skilled in art, that applicant, as of filing date sought, was in possession of invention, with invention being, for purposes of "written description" inquiry, whatever is presently claimed."
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision.
With respect to the present invention, the claims fail to meet the written description requirement because the claims encompass a significantly large genus of mutations which are not described in the specification.
Claim Rejections - 35 USC § 112(a) - Enablement
9. Claims 12, 13, 17, 25, 31, 38, 42, 49, 50, 56, 63, 83 and 133-137 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 methods comprising assaying a nucleic acid sample from an individual having cancer and detecting in the sample a mutation in the CD274 gene encoding for an R260H missense mutation,
does not reasonably provide enablement for the claimed methods which obtaining knowledge of or detecting any mutation in a CD274 gene in any individual and then administering to the individual any anti-cancer therapy, including methods wherein the undefined mutation results in low or no or high expression of PD-L1 protein in the cancer (claim 38); methods wherein the undefined mutation reduces the interaction between a PD-L1 polypeptide encoded by the CD274 gene and a PD-1 receptor; and/or e reduce the activity of a PD-Li polypeptide encoded by the CD274 gene (claim 39); or wherein the undefined mutation results in an immune checkpoint inhibitor resistant cancer (claim 50).
The following factors have been considered in formulating this rejection (In re Wands, 858F.2d 731, 8 USPQ2d 1400 (Fed. Cir. 1988): the breadth of the claims, the nature of the invention, the state of the prior art, the relative skill of those in the art, the predictability or unpredictability of the art, the amount of direction or guidance presented, the presence or absence of working examples of the invention and the quantity of experimentation necessary.
Claims 12 and 13 broadly encompass methods of treating or delaying progression of cancer, comprising, responsive to acquiring knowledge of any one or more mutations in a CD274 gene in a sample from an individual, administering to the individual an effective amount of a treatment that comprises any anti-cancer therapy.
Claim 17 broadly encompasses a method of treating or delaying progression of cancer, comprising: detecting any one or more mutations in a CD274 gene in a sample from an individual; and administering to the individual an effective amount of a treatment that comprises any anti-cancer therapy.
With the exception of claims 31 and 42, the claims do not define the mutation in the CD274 gene. Thus, the claims encompass methods that detect any single nucleotide or multiple nucleotide insertion, deletion or substitution or any rearrangement of gene fusion even involving a portion of the CD274 gene and then administer any anti-cancer treatment to the subject based on / i.e.. “responsive to” obtaining the information regarding the occurrence of the mutation.
While the elected species in claims 31 and 42 are limited to methods which detect the R260H mutation, these claims (as well as the remaining claims) encompass methods in which the mutation leads to low or no or high expression of PD-L1 protein in the cancer (claim 38); methods wherein the undefined mutation reduces the interaction between a PD-L1 polypeptide encoded by the CD274 gene and a PD-1 receptor; and/or e reduce the activity of a PD-Li polypeptide encoded by the CD274 gene (claim 39); or wherein the undefined mutation results in an immune checkpoint inhibitor resistant cancer (claim 50).
Regarding the elected R260H missense mutation in the CD274 gene, the specification teaches that this mutation occurred in cancers in which there was low or no PD-L1 expression, as determined by IHC (e.g., para [0590]):
Regarding treatment of cancer patients with the R260H mutation, the specification (para [0590]) states:
“Interestingly, of the eleven R260H cases concurrently tested with PD-L1 IHC, most showed little to no PD-L1 expression, suggesting that patients with R260H mutations might not be treated with ICPI if only tested with PD-L1 IHC.”
However, the specification does not clearly teach that in response to obtaining information or detecting a R260H CD274/PD-L1 mutation, a cancer patient should be administered an immune checkpoint inhibitor therapy or that the cancer patient should be administered any other particular therapy. The specification at para [0072] does state “Without wishing to be bound by theory, it is thought that CD274 mutations associated with low or no PD-L1 expression can act as resistance biomarkers for ICPI due to, for example and without limitation, the lack of PD-L1 protein present on the tumor cells, and/or loss of affinity for binding of PD-L1 antibodies used to detect PD-L1 protein expression and therefore loss of affinity for binding of anti-PD-L1 therapies.” Yet, the specification does not clearly teach that if the R260H mutation is detected in a nucleic acid sample from the individual, in the absence of PD-L1 IHC testing, then the individual should be administered an anti-PD-L1 therapy, or any immune checkpoint inhibitor, or any cancer immunotherapy or any small molecule inhibitor or an anti-inflammatory therapy etc.
Similarly, the specification does not provide sufficient guidance as to what anti-cancer therapy is to be administered to cancer patients following the detection of any undefined mutation or any other particular mutation, alone or in combination with knowledge regarding a lack of expression or low or high expression of PD-L1. Note that the specification at para [0010] states that the claimed invention encompasses methods “wherein the presence of the one or more mutations in the CD274 gene in the sample identifies the individual as one who may or may not benefit from the anti-cancer therapy.” Further, para [0013] states “the presence of the one or more mutations in the CD274 gene in the sample identifies the individual as one who may have a cancer that is resistant to one or more immune checkpoint inhibitors.” That is, the claims are not considered to be directed to methods that detect a mutation in the CD274 gene as indicative of cancer per se, but rather detect the mutation in the CD274 gene as indicative of whether the individual will benefit from / be responsive to or not benefit from / be resistant to a particular anti-cancer therapy.
Regarding claim 49, the specification (para [0592]) states:
“CD274 missense mutations could mediate resistance to ICPI due to potential steric or affinity-altering interferences in the binding of the PD-L1 ligand to the PD-1 receptor, similar to a resistance mechanism described for ROS1 (Huang et al., JTO Clinical and Research Reports (2020) 100100; Huang et al., Int J Cancer (2021) 148(7):1778-1788). A slightly lower level of PD-L1 IHC staining in the cases with CD274 missense mutations was observed, when compared to cases without CD274 mutations. In addition, a significantly lower PD-L1 IHC staining in the clonal missense mutations was observed, when compared to the sub-clonal missense mutations. This could be due to the lower rates of PD-L1 antibody binding (from the IHC assay) to the PD-L1 ligand on the tumor cells instead of actual lower PD-L1 protein expression. No correlation between the predicted functional status of missense mutations and PD-L1 IHC expression was observed.”
Accordingly, the specification does not appear to teach that the R260H or a representative number of alternative mutations in CD274 are correlated with a reduction in the interaction between a PD-L1 polypeptide encoded by the CD274 gene having a mutation and a PD-1 receptor or a reduction in PD-L1 activity.
Regarding claims 12, 13, 17, 25, 38, 49, 50, 56, 63, 83 and 133-137, again these claims do not define the CD274 mutation in terms of any particular structural properties or any other relevant identifying characteristics. While the specification discloses additional CD274 mutations (e.g., Table 1 lists missense mutations, truncations, splice site mutations and insertions/deletions in the CD274 gene), it does not appear that the specification teaches a representative number of the diverse types of mutations that can occur in CD274 in cancers. This finding is supported by the teachings of Murugesan et al (20240410016; co-authored by one of the present inventors) which teaches a large number of CD274 rearrangements – i.e., mutations (see Tables 1-3 therein) characterized as being indicative of responsiveness to immune checkpoint inhibitor therapy, which mutations are not disclosed in the present application. Note that para [0155] of the present specification states “the one or more mutations comprise one or more of a genomic rearrangement, an alteration in a promoter, a gene fusion, or a copy number alteration;” and para [0159] states: “In some embodiments, the one or more CD274 mutations comprise a CD274 intragenic rearrangement.” Further, the specification does not indicate which of the mutations listed therein are associated with responsiveness to any anti-cancer therapy or to particular cancer therapies, including an immune therapy, or which mutations are correlated with expression levels of PD-L1 protein or with the activity of PD-L1 or the interaction of PD-L1 with a PD-1 receptor.
The unpredictability of determining the effect of a mutation on the function of the encoded PD-L1 protein is supported by the above teachings of the specification (para [0590]):
“While most of the non-truncating SV CD274 mutations had low to no tumor cell expression of PD-L1, the expression levels of PD-L1 differed among the various CD274 SV mutation categories. Interestingly, of the eleven R260H cases concurrently tested with PD-L1 IHC, most showed little to no PD-L1 expression, suggesting that patients with R260H mutations might not be treated with ICPI if only tested with PD-L1 IHC. This contrasted with the five E237K cases, where most cases had some PD-L1 expression, suggesting that the E237K has little to no effect on PD-L1 protein expression. Most other variants were only observed in a single sample (with or without concurrent PD-L1 expression data) due the rarity of the mutations.”
The art of identifying novel mutations, and particularly of determining an association between mutations and a phenotype, such as response to a particular anti-cancer agent, including an immune checkpoint inhibitor, is highly unpredictable. Knowledge of the sequence of the wildtype CD274 gene does not allow one to predict the identity of mutations in this gene or ascertain which of those mutations may be correlated with responsiveness to anti-cancer therapy. No clear structure-function relationship is disclosed in the specification which would allow one to predict which mutations are correlated with responsiveness to a representative number of the diverse therapies encompassed by the claims, including any cancer immunotherapy.
It was well recognized in the art at the time the invention was made that the associations between mutations / genetic alterations and phenotypic traits are often not reproducible.
For example, the claims as broadly written encompass methods wherein the mutation is a polymorphism. The unpredictability of establishing a correlation between a polymorphism and a phenotype is well accepted in the art. For example, Cohen et al (Shock. 2020 March. 53(3): 256-268) teaches that recent studies suggest “that a large portion of SNP studies are not reproducible” (abstract). Cohen (p. 2) further states that:
“With approximately 4–5 million SNPs in the human genome (i.e. gene sequence variations with >1% frequency in the human population (18, 19)), the possibility of spurious SNP-disease associations is a major concern; thus, we suggest that the ultimate clinical utility of assessing particular SNPs will likely depend on validation and quality control (QC) measures. Additionally, the interplay between SNPs and pathology, physiologic responses, and pharmaceuticals all contribute to clinical outcomes.
Illustrating the crucial need for validation in SNP studies, a well-powered replication and validation study of 70 previously published studies of SNPs associated with clinical outcomes after blood or marrow transplantation found only one validated SNP of the 45 SNPs studied.”
Extensive experimentation would be required to identify new mutations or screen the mutations listed in Tables 1-4 and 6 to ascertain which mutations would be indicative of a patient’s likelihood to respond to a particular cancer therapy. For example, such experimentation may involve sequencing the CD274 gene in individuals having a representative number of different types of cancer to identify CD274 mutations, determining if the mutations have a functional effect on the encoded PD-L1 protein’s activity or ability to bind to PD-1, and / or an effect on expression levels of PD-L1 (intracellularly or on a cancer cells surface or in soluble form), and then performing assays to determine if such mutations are correlated with responsiveness to a representative number of anti-cancer therapies, such as responsiveness to a representative number of diverse small molecule inhibitors (i.e., small molecules that inhibit any target). Such experimentation would also encompass determining which of the large number of missense mutations listed in Tables 1-4 and 6 are correlated with responsiveness to a representative number of anti-cancer therapies, such as responsiveness to a representative number of diverse small molecule inhibitors or an anti-inflammatory therapy or a cancer immunotherapy. The results of performing such experimentation are unpredictable. Thereby the experimentation required to practice the broadly claimed invention is undue.
As set forth in Rasmusson v. SmithKline Beecham Co., 75 USPQ2d 1297, 1302 (CAFC 2005), enablement cannot be established unless one skilled in the art "would accept without question" an Applicant's statements regarding an invention, particularly in the absence of evidence regarding the effect of a claimed invention. Specifically:
"As we have explained, we have required a greater measure of proof, and for good reason. If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to "inventions consisting of 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. That scenario is not consistent with the statutory requirement that the inventor enable an invention rather than merely proposing an unproved hypothesis."
Case law has established that '(t)o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation.'" In re Wright 990 F.2d 1557, 1561. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) it was determined that '(t)he scope of the claims must bear a reasonable correlation to the scope of enablement provided by the specification to persons of ordinary skill in the art". The amount of guidance needed to enable the invention is related to the amount of knowledge in the art as well as the predictability in the art. Furthermore, the Court in Genetech Inc. v Novo Nordisk 42 USPQ2d 1001 held that '(I)t is the specification, not the knowledge of one skilled in the art that must supply the novel aspects of the invention in order to constitute adequate enablement".
Herein, although the level of skill in the art is high, given the lack of disclosure in the specification and in the prior art and the unpredictability of the art, it would require undue experimentation for one of skill in the art to make and use the invention as broadly claimed.
Double Patenting
9. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 12, 13, 17, 25, 38, 49, 56, 63, 83 and 133-137 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of copending Application No.18/699,569 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the present claims and the claims of ‘569 are both inclusive of methods comprising detecting or obtaining information regarding a mutation, including a gene fusion, involving the CD274 gene in a nucleic acid sample from a subject having cancer and then, responsive to the detecting or obtaining information regarding the mutation, administering an anti-cancer therapy to the subject (e.g., claims 10-12), including administering an immune checkpoint inhibitor to the subject (i.e., a cancer immunotherapy; see claims 2 and 5 of ‘569).
Regarding dependent claims 13, 17, 25, 38, 49, 56, 63, 83 and 136-137, the claims of ‘569 recite that the cancer is colorectal carcinoma (claim 6); that the clonality of the CD274 nucleic acid is determined (claim 15 of ‘569) and that the mutation is sub-clonal (e.g., claim 16 and 22of ‘569); methods that further comprise enriching for nucleic acid molecules comprising the mutation (e.g., claims 26 and 27); and methods that further comprise determining expression levels of CD274/PD-L1, including by performing immunohistochemistry of tumor cells, to detect high expression or no expression (e.g., claims 5, 16, 22, and 25 of ‘569).
Regarding claims 134-135, the claims of ‘569 do not recite that less than 50% of the tumor cells in the sample are predicted to have the mutation, particular based on a variant allele fraction. However, claims 16 and 22 recite that it is determined that the nucleic acid molecule comprising the mutation / rearrangement is sub-clonal in the cancer. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of ‘569 so as to have determined the frequency of the mutation / rearrangement in the tumor cells, and to have detected cancers having the mutation / rearrangement in less than 50% of the tumor cells in order to further characterize the sub-clonal nature of the mutation in the cancer..
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Rejections - 35 USC § 102
10. 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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 12, 13, 17, 25, 38, 56, 63, 83, 136 and 137 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ogawa et al (EP3290517).
Ogawa teaches methods comprising analyzing a nucleic acid sample from a subject having cancer and detecting he occurrence of a structural abnormality (i.e., a mutation), including deletions, tandem duplications, inversions and translocations, in the CD274 / PD-L1 gene (para [0006]). It is disclosed that the majority of the structural abnormalities include a deletion of the 3’UTR of the CD274 / PD-L1 gene and that a deletion of 3’-UTR sequences results in an increase in expression of PD-L1 on the surface of cancer cells(para [0006]). Ogawa (para [0006]) states:
“As a result, it was found that the same abnormality is present in various types of malignant tumors such as stomach cancer, lung cancer, large intestinal cancer, cervical cancer, malignant melanoma and B cell lymphoma. This result suggests that a structural abnormality, i.e., a deletion of 3'UTR of PD-L1 accompanied by high expression of PD-L1 is a common abnormality occurring in various types of malignant tumors.”
It is disclosed that the methods therein encompass:
“A method of predicting whether or not PD-1/PD-L1 blockade is effective for treatment of a subject suffering from malignant tumor, which comprises detecting abnormality of genome relating to effectiveness of the PD-1/PD-L1 blockade in a tumor cell that has been taken from the subject and evaluating the PD-1/PD-L1 blockade as useful for the treatment of the subject when there is the abnormality.” (para [0008]).
It is also stated that the abnormality in the CD274 / PD-L1 gene may be a partial or complete deletion of the 3’-UTR (“[3]” at para [0008]) or a complete or partial truncation that includes exon 5, exon 6, exon 7 of a PD-L1 transcript (e.g., “[5]” and “[6]” in para [0008]).
Ogawa teaches administering an immune checkpoint inhibitor, such as an anti-PD-L1 or anti-PD-1 antibody to the subject (e.g., para [0038]).
Accordingly, with respect to claim 17, Ogawa teaches a method of treating cancer, comprising:(a) detecting one or more mutations in a CD274 gene in a sample from an individual; and (b) administering to the individual an effective amount of a treatment that comprises an anti-cancer therapy – i.e., the cancer immunotherapy of anti-PD-L1 or anti-PD-1 inhibitor.
Further, with respect to claims 12 and 13, by detecting the mutation / structural abnormality in the CD274 / PD-L1 gene, the method of Ogawa is necessarily one that acquires knowledge regarding a mutation in the CD274 / PD-L1 gene in a sample from an individual, and responsive to acquiring the knowledge, administering an effective anti-cancer therapy to the individual.
Regarding claim 25, as discussed above, Ogawa teaches administering the cancer immunotherapy of an anti-PD-L1 or anti-PD-1 inhibitor (e.g., para [0038]) to the individual determined to have the structural abnormality / mutation.
Regarding claim 38, as discussed above, Ogawa teaches that the method is one that further assays and detects a high expression level of PD-L1 protein on the surface of the cancer cells from the subject (e.g., para [0006]).
Regarding claim 56, Ogawa (para [0030-0031] teaches:
“The abnormal PD-L1 gene expression can be detected by measuring PD-L1 mRNA in a tumor cell by use of a (semi) quantitative PCR, such as RQ-PCR and RT-PCR. RQ-PCR is a method of continuously detecting accumulation of a PCR product during a PCR process, thereby enabling easy and accurate quantification in the exponential phase in the beginning of PCR.
The probe or primer to be used in the above methods, consists of a nucleotide fragment (preferably a DNA fragment) consisting of a nucleotide sequence containing a genomic abnormality site relating to acceleration of PD-L1 gene expression; a nucleotide sequence complementary to the nucleotide sequence or a sequence capable of hybridizing with either one of these sequences under stringent conditions.”
By performing PCR to amplify nucleic acids comprising the mutation, the method of Ogawa enriches the sample for nucleic acids comprising the mutation.
Regarding claim 63, Ogawa teaches that the cancer includes colon adenocarcinoma (para [0075] and [0098]), as well as colorectal adenocarcinoma (CRC; para [0073]; see also para [0018]).
Regarding claim 83, Ogawa teaches that the CD274 / PD-L1 structural abnormality / mutation is detected in a tumor cell from the subject (e.g., para [0008]) or in DNA isolated from a tumor cell from a subject (e.g., para [0016]).
Regarding claims 136 and 137, Ogawa teaches that the expression of PD-L1 was determined by performing immunohistochemical staining (e.g., para [0008] at “[11]” and claim 4; see also para [0006]).
Claim Rejections - 35 USC § 103
11. 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) 133-135 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ogawa et al (EP3290517) in view of Liu et al (Nature Medicine. Dec. 2019. 25: 1916-1927).
The teachings of Ogawa are presented above. Ogawa does not teach that the mutation is a sub-clonal mutation (claim 133), that less than 50% of tumor cells in the sample are predicted to have the mutation (claim 134) or that the less than 50% of tumor cells predicted to have the mutation is based on variant allele fraction or tumor purity (claim 135).
However, Liu teaches methods of detecting “mutation clonality” – i.e., mutations that are sub-clonal and mutations that are clonal in tumors of subjects that have been treated with immune checkpoint inhibitor therapy (e.g., Figure 1a and legend). It is stated (p. 1918 at col. 1) that:
“Overall, 39% of tumors had BRAF mutations, 30% had NRAS mutations and 17% had NF1 mutations (Fig. 1a). The median tumor purity (the proportion of sample DNA from tumor cells) was 0.67 (IQR 0.46–0.83) and the median tumor heterogeneity (the proportion of subclonal mutations) was 0.17 (IQR 0.12–0.25). The median purity-corrected tumor ploidy (Methods) was 2.15 (IQR 2.01–3.12), with 38% of tumors inferred to have genome doubling, consistent with previous reports.”
Liu calculated variant allele frequency of the mutations to determine the purity of the tumors – e.g., “Purity and ploidy. Purity and ploidy were estimated using the ABSOLUTE algorithm67, which integrates variant allele frequency distributions and copy number variants to estimate absolute tumor purity and ploidy and infer the
cancer cell fraction, the proportion of cancer cells in the sample that contain each
mutation. Allelic segments following purity and ploidy correction were used to
estimate allelic copy number” (p. 1928, col. 2).
Liu also calculated the tumor heterogeneity, defined as the proportion of subclonal mutations in each tumor, in responders and non-responders/progressors (Figure 2 and legend).
Liu (p. 1925, col. 2, final para) also teaches:
“Tumor heterogeneity (the proportion of subclonal mutations) has previously been associated with poor prognosis across multiple tumor types and therapies. High heterogeneity suggests a highly mutagenic disease and a high degree of subclonality, with a higher likelihood of preexisting or rapidly evolving resistant clones.”
It would have been obvious to one of ordinary skill in the art at the time the invention was made to have modified the method of Ogawa so as to have further included a step of determining if the mutations were subclonal, including if less than 50% of the tumor cells harbored the CD274 mutation, particularly by determining the variant allele fraction and/or tumor cell purity, as taught by Liu. One would have been motivated to have done so because Liu teaches that the presence of subclonal mutations is indicative of a poor prognosis and may indicate a higher likelihood of rapidly evolving clones. Accordingly, one would have made such a modification of the method of Ogawa in order to have provided additional information regarding the tumor and the prognosis of the cancer patient.
12. Claim(s) 12, 13, 17, 25, 38, 49, 50, 56, 63, 83, 136 and 137 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gong et al (J. Exp. Med. 2019.216(4): 982-1000 and Supplemental Material, 25 pages total).
Gong (e.g., p. 995-996, col. 1 and p. 983, col. 1) teaches a method comprising assaying a nucleic acid sample to detect the presence of a CD274 / PD-L1 mutation – i.e., a splice variant that results in an encoded protein lacking a transmembrane domain. Gong (p. 983, col. 1) states:
“we identified two unique secreted PD-L1 (sPDL1) splicing variants lacking the transmembrane domain from two NSCLC patients who failed to respond to aPD-L1 treatment. From the additional RNA sequencing (RNA-seq) analysis conducted with post-treatment specimens obtained from 15 patients who were refractory to PD-L1 blockade therapy, we further found that two patients harbored the same sPD-L1 splicing
variants. These sPD-L1 variants competitively interrupted the neutralizing activity of aPD-L1 antibody in vitro and induced resistance to aPD-L1 therapy in a MC38 syngeneic mouse model.”
Gong does not specifically teach that upon determining / obtaining knowledge of the presence of the secreted PD-L1 splicing variants in a sample from an individual having cancer, that the individual is administered an anti-cancer therapy.
However, Gong (p. 995, col. 1) does teach:
“Consistent with these results, the levels of soluble PD-L1 in plasma and pleural effusion from patients who harbored sPD-L1 splicing variants were significantly
higher than those in patients without the variants. We also demonstrated in vivo that aPD-1 antibody treatment overcame the resistance induced by the sPD-L1 variants. Taken together, these findings suggest that the presence of sPD-L1 splicing variants or the level of soluble PD-L1 in plasma or pleural effusion may work as a biomarker to predict a patient’s response to PD-L1 blockade therapy and that aPD-1 antibody treatment could be a therapeutic option to overcome sPD-L1 variant-induced
resistance.”
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Gong so as to have administered the anti-cancer therapy of an anti-PD1 antibody to those cancer patients determined to have one of the sPD-L1 splicing variants because Gong teaches that the anti-PD1 antibody therapy was effective at overcoming the resistance to anti-PD-L1 antibody therapy induced by the sPD-L1 splicing variants.
Regarding claim 25, modification of the method of Gong so as to have administered an anti-PD1 antibody therapy would have resulted in a method in which the cancer patient was administered a cancer immunotherapy.
Regarding claim 38, Gong (p. 983, col. 1) states “the levels of soluble PD-L1 in the plasma or pleural effusion in patients detected with sPD-L1 splice variants were much higher than in healthy donors or patients without the sPD-L1 variants.” Thus Gong teaches detecting a high level of expression of soluble PD-L1 protein in subjects harboring the soluble/secreted splicing variants of PD-L1. Note that claim 38 does not specify a particular type or form of PD-L1 protein whose expression level is determined.
Regarding claim 49, the secreted splicing variants of PD-L1 disclosed by Gong are considered to have the property of reducing an activity of PD-L1 – i.e., expression on the surface of the cancer cell due to the loss of the transmembrane region. Note that claim 49 does not specify any particular activity of the PD-L1 polypeptide.
Regarding claim 50, as discussed above, the secreted splicing variants of PD-L1 cause resistance to anti-PD-L1 antibody therapy and thereby to an immune checkpoint inhibitor therapy.
Regarding claim 56, Gong teaches performing targeted PCR amplicon sequencing to detect the secreted splicing variants of PD-L1 (e.g.., p. 983, col. 2, second para; and p. 996, col. 1). By performing PCR to amplify nucleic acids comprising the PD-L1 mutation, the method of Gong enriches the sample for nucleic acids comprising the mutation.
Regarding claim 63, Gong does not teach a method wherein the cancer patient has colon adenocarcinoma (i.e., the elected species of cancer).
However, Gong does teach that PD-L1 is abundantly expressed in colon carcinoma cells (P. 982, col. 1). At p. 988, col. 1, Gong also teaches:
“we produced mouse PD-L1 variants (mPD-L1v242 and mPD-L1v178), which have the same human PD-L1 truncation by aberrant splicing (Fig.S4),and overexpressed them in MC38, a cell line from C57BL/6 murine colon adenocarcinoma cells which has been reported to have high PD-L1 expression induced by IFN-γ and a response to the blockade of the PD-1/PD-L1 axis (Juneja et al., 2017). Through the administration of aPD-L1 antibody to mice bearing MC38, MC38/cont, MC38 overexpressing mouse PD-L1 (MC38/mPD-L1), MC38/mPD-L1v242, and MC38/mPD-L1v178 (Fig. 8 A), we confirmed that MC38/mPD-L1v242 was resistant to
aPD-L1 antibody treatment and the median survival was shorter than that of MC38.”
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have applied the method of Gong to other cancers, including colon adenocarcinoma because Gong teaches that this type of cancer has a strong expression level of PD-L1 and a mouse model carrying one of the secreted splicing variants of PD-L1 was found to develop resistance to anti-PD-L1 therapy.
Regarding claim 83, Gong teaches that the secreted splicing variants of PD-L1 were detected in nucleic acid samples from tumor tissues (e.g., p. 995 to p. 996, col. 1).
Regarding claims 136 and 137, Gong teaches that the expression of PD-L1 was determined by performing flow cytometry (p. 996, col. 2) or by immunohistochemical staining (e.g., p. 997, col. 1).
13. Claim(s) 133-135 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gong et al (J. Exp. Med. 2019.216(4): 982-1000) in view of Liu et al (Nature Medicine. Dec. 2019. 25: 1916-1927 and Supplemental Material, 25 pages total).
The teachings of Gong are presented above. Gong does not teach that the mutation is a sub-clonal mutation (claim 133), that less than 50% of tumor cells in the sample are predicted to have the mutation (claim 134) or that the less than 50% of tumor cells predicted to have the mutation is based on variant allele fraction or tumor purity (claim 135).
However, Gong (p. 988) teaches that the number of cancer cells harboring the sPD-L1 variants can be low. It is stated that:
“To further investigate whether a small fraction of cancer cells that harbor sPD-L1variants would protect the whole tumor from attack by cytotoxic lymphocytes, we tested the PD-L1 blockade antibody in mice subcutaneously injected with a mix of MC38/PD-L1v242 and MC38/PD-L1-WT in various ratios. Unexpectedly, a mixture of only 1%ofcells expressing PD-L1v242 and 99% of cells expressing PD-L1-WT successfully induced PD-L1 blockade resistance (Fig. 9 A), even though the level of soluble PD-L1 in plasma was low on day 7 (the first day of treatment).” See also p. 994, col. 2) does teach “a mixture of only 1% MC38 cells with sPD-L1 variants (MC38/mPD-L1v242) and 99% of cells that overexpressed wild-type PD-L1 (MC38/mPD-L1) were found to cause resistance to PD-L1 blockade therapy by accumulation of soluble PD-L1 in the tumor and plasma.”
Thus, the teachings of Gong suggest that the secreted splicing variant of PD-L1 induces resistance to anti-PD-L1 antibody thereby when it is present as a subclonal mutation.
Further, Liu teaches methods of detecting “mutation clonality” – i.e., mutations that are subclonal and mutations that are clonal in tumors of subjects that have been treated with immune checkpoint inhibitor therapy (e.g., Figure 1a and legend). It is stated (p. 1918 at col. 1) that:
“Overall, 39% of tumors had BRAF mutations, 30% had NRAS mutations and 17% had NF1 mutations (Fig. 1a). The median tumor purity (the proportion of sample DNA from tumor cells) was 0.67 (IQR 0.46–0.83) and the median tumor heterogeneity (the proportion of subclonal mutations) was 0.17 (IQR 0.12–0.25). The median purity-corrected tumor ploidy (Methods) was 2.15 (IQR 2.01–3.12), with 38% of tumors inferred to have genome doubling, consistent with previous reports.”
Liu calculated variant allele frequency of the mutations to determine the purity of the tumors – e.g., “Purity and ploidy. Purity and ploidy were estimated using the ABSOLUTE algorithm67, which integrates variant allele frequency distributions and copy number variants to estimate absolute tumor purity and ploidy and infer the
cancer cell fraction, the proportion of cancer cells in the sample that contain each
mutation. Allelic segments following purity and ploidy correction were used to
estimate allelic copy number” (p. 1928, col. 2).
Liu also calculated the tumor heterogeneity, defined as the proportion of subclonal mutations in each tumor, in responders and non-responders/progressors (Figure 2 and legend).
Liu (p. 1925, col. 2, final para) also teaches:
“Tumor heterogeneity (the proportion of subclonal mutations) has previously been associated with poor prognosis across multiple tumor types and therapies. High heterogeneity suggests a highly mutagenic disease and a high degree of subclonality, with a higher likelihood of preexisting or rapidly evolving resistant clones.”
It would have been obvious to one of ordinary skill in the art at the time the invention was made to have modified the method of Gong so as to have further included a step of determining if the secreted PD-L1 variants / mutations were sub-clonal, including if less than 50% of the tumor cells harbored the variants / mutation, particularly by determining the variant allele fraction and/or tumor cell purity, as taught by Liu. One would have been motivated to have done so because Liu teaches that the presence of subclonal mutations can be indicative of a poor prognosis and may indicate a higher likelihood of rapidly evolving clones. Accordingly, one would have made such a modification of the method of Gong in order to have provided additional information regarding the tumor and the prognosis of the cancer patient.
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/CARLA J MYERS/Primary Examiner, Art Unit 1682
