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 .
Claim Status
Applicant’s amendments and remarks, filed 06/22/2026, are acknowledged.
Claims 5, 6, 10, 11, 16, and 19-21 are canceled.
Claims 1-4 and 12-15 are amended.
Claims 1-4, 7-9, 12-15, 17-18, and 22-24 are pending.
As such, claims 1-4, 7-9, 12-15, 17-18, and 22-24 are pending examination and currently under consideration for patentability under 37 CFR 1.104.
DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06/22/2026 has been entered.
Withdrawn Objections
The claim objections are withdrawn. Issues regarding minor informalities have been sufficiently addressed through amendments to the claims filed on 06/22/2026.
The drawing objections are withdrawn. Issues regarding minor informalities have been sufficiently addressed through amendments to the specification on 06/22/2026.
The sequence disclosure objections are withdrawn. Issues regarding the file comprising a non-compliant CRF has been sufficiently addressed through amendments to the sequence listing and specification on 06/22/2026.
Maintained Rejections
Claim Rejections – 35 USC § 112(a) Written Description
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 1-4, 7-9, 17, 18, and 22-24 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claim 1 is drawn to a method comprising steps of: administering an immunotherapy to a subject suffering from cancer who has received a prior immunotherapy and has a human leukocyte antigen (HLA) class I (HLA-I) evolutionary divergence (HED) above an average HED of a population of subjects suffering from the cancer; wherein the HED of the subject is determined by quantifying the sequence divergence between an HLA-A gene, an HLA-B gene, and an HLA-C gene through measurement of the Grantham distance; and wherein the immunotherapy is a programmed cell death protein 1 (PD-1) blockade therapy, a programmed cell death protein ligand 1 (PD-L1) blockade therapy, and/or a cytotoxic T lymphocyte-associated protein 4 (CTLA-4) blockade therapy; wherein the immunotherapy is a monoclonal antibody or antigen-binding component thereof.
Claim 2 is drawn to a method comprising steps of: sequencing an HLA-A gene, an HLA-B gene, and an HLA-C in a subject suffering from cancer who has received a prior immunotherapy; determining an HED of the subject by quantifying the sequence divergence between an HLA-A gene, an HLA-B gene, and an HLA-C gene through measurement of the Grantham distance; and identifying the subject as a candidate for treatment with an immunotherapy when the HED of the subject is above an average HED of a population of subjects suffering from the cancer; wherein the immunotherapy is a programmed cell death protein 1 (PD-1) blockade therapy, a programmed cell death protein ligand 1 (PD-L1) blockade therapy, and/or a cytotoxic T lymphocyte-associated protein 4 (CTLA-4) blockade therapy; wherein the immunotherapy is a monoclonal antibody or antigen-binding component thereof.
Claim 3 is drawn to a method of treating a subject suffering from cancer comprising: determining that the subject, who has received a prior immunotherapy and has an HED above an average HED of a population of subjects suffering from the cancer; wherein the HED of the subject is determined by quantifying the sequence divergence between an HLA-A gene, an HLA-B gene, and an HLA-C gene through measurement of the Grantham distance; administering an immunotherapy; and wherein the immunotherapy is a PD-1 blockade therapy, a PD-L1 blockade therapy, and/or a CTLA-4 blockade therapy; wherein the immunotherapy is a monoclonal antibody or antigen-binding components thereof.
Claim 4 is drawn to a method of determining if a subject suffering from cancer will respond to an immunotherapy comprising: sequencing an HLA-A gene, an HLA-B gene, and an HLA-C gene in the subject, who has received a prior immunotherapy; and determining an HED of the subject by quantifying the sequence divergence between an HLA-A gene, an HLA-B gene, and an HLA-C gene through measurement of the Grantham distance; and wherein when the HED of the subject is above an HED of a population of subjects suffering from the cancer indicates the subject will respond to the immunotherapy; wherein the immunotherapy is a programmed cell death protein 1 (PD-1) blockade therapy, a programmed cell death protein ligand 1 (PD-L1) blockade therapy, and/or a cytotoxic T lymphocyte-associated protein 4 (CTLA-4) blockade therapy; wherein the immunotherapy is a monoclonal antibody or antigen-binding component thereof.
Claim 7 is drawn to the method of claim 1, wherein the HED of the subject is determined as the mean evolutionary divergence between all of the HLA-A gene, HLA-B gene, and the HLA-C gene.
Claim 8 is drawn to the method of claim 1, wherein the cancer is a solid tumor.
Claim 9 is drawn to the method of claim 1, wherein the cancer is melanoma or non-small cell lung cancer.
Claim 17 is drawn to the method of claim 1, wherein the subject is heterozygous for the HLA-A gene, the HLA-B gene, and the HLA-C gene.
Claim 18 is drawn to the method of claim 1, wherein the subject further has a tumor mutational burden at or above the top quartile of tumor mutational burdens of individuals of subjects suffering from the cancer.
Claim 22 is drawn to the method of claim 2, wherein the HED is of the subject is determined as the mean evolutionary divergence between all of the HLA-A gene, the HLA-B gene, and the HLA-C gene.
Claim 23 is drawn to the method of claim 4, wherein the HED is of the subject is determined as the mean evolutionary divergence between all of the HLA-A gene, the HLA-B gene, and the HLA-C gene.
Claim 24 is drawn to the method of claim 1, wherein the population of subjects suffering from the cancer have received the prior immunotherapy.
The specification discloses that the term “treatment” (also “treat” or “treating”) refers to any administration of a substance that partially or completely alleviates, ameliorates, relieves, inhibits, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms, features, and/or causes of a particular disease, disorder, and/or condition (e.g., cancer) (see [0076]).
Additionally, Example 1 disclose of evolutionary divergence of HLA-I genotype impacts efficacy of cancer therapy. Particularly, the specification discloses of determining the germline HED of patients with melanoma and non-small cell lung cancer treated with an immune checkpoint inhibitor (ICI) by quantifying the physiochemical sequence divergence between HLA-I alleles of each patient’s genotype (see [0132]). For each patient, the HED at each of HLA-A, HLA-B, and HLA-C by measuring the Grantham distance between the peptide-binding domains of the two alleles; the Grantham distance is a classic metric that allows quantification of physiochemical differences between protein amino acid sequences, taking into account composition, polarity, and volume (see [0133]). Hierarchical clustering of HED per locus for all pairwise allele combinations across HLA-A, HLA-B, and HLA-C was performed, and it demonstrated distinct clusters of high and low divergence between alleles (see Fig. 1b, Fig. 5a-5c) as expected and consistent with known relationships between HLA-A, HLA-B, and HLA-C loci (see [0133]). It also showed that HLA-B pairwise divergences are higher relative to HLA-A and HLA-C consistent with prior reports that HLA-B is the oldest and most diverse of the three HLA-I loci (see [0133]). Moreover, HLA-C alleles had the lowest pairwise divergences, in line with prior studies that HLA-C has evolved most recently (see [0133]). The mean HED distributions in patients from the cohorts were similar to those observed in the TCGA cohorts, wherein prior comparison of the Grantham distance to other common metrics of sequence divergence showed that the Grantham distance best captured the functional properties of HLA-I molecules (see [0133]). With respect to whether HED is associated with response to ICI, the patients were stratified by mean HED in a cohort of 100 patients with melanoma treated with anti-CTLA-4, and observed improved overall survival after ICI therapy in patients with high mean HED which was similar across different metrics used to combine pairwise divergences of HLA-A HLA-B, and HLA-C alleles (see [0134]). It was also found that the effect of mean HED on survival was independent of tumor mutational burden (TMB) and other relevant genomic and clinical variables; and, both high mean HED and high TMB on overall survival after ICI was more pronounced than the effect of either alone, as reflected by the reduction in hazard ratio (see [0134]). Particularly, it was found that high mean HED was associated with improved survival after ICI in the 78 fully heterozygous patients (see [0135]). In a second cohort of 76 fully heterozygous patients with NSCLC treated with anti-PD-1, it was found that high mean HED was associated with better overall survival (see [0135]). This was also observed in an additional third cohort of 95 fully heterozygous patients with metastatic melanoma treated with anti-PD-1 (see [0135]). In a combined analysis of all three cohorts, it was found that an increase in mean HED corresponds to improved overall survival; and, beyond survival, clinical response to ICI was also associated with high mean HED when considering all patients (HLA-I homozygotes or heterozygotes) or only fully heterozygous patients (see [0135]-[0137]).
The specification also discloses that patients with renal cell carcinoma (RCC) with high mean HED demonstrate increased progression free survival after treatment with a combination therapy; specifically, RCC patients treated with a combination of Lenvatinib plus pembrolizumab showed increased progression free survival (see [0138]).
However, the specification fails to disclose that Applicant was in possession of the claimed methods. Particularly, the specification fails to disclose that Applicant was in possession of treating the large genera of cancers encompassed by the claims with any immunotherapy. Specifically, the specification fails to disclose that Applicant was in possession of any immunotherapy except those in claims 12-15. The specification fails to disclose that Applicant was in possession of the genus of PD-1/PD-L1 blockade therapies and/or CTLA-4 blockade therapies which are all defined entirely by function. Additionally, the specification fails to disclose that Applicant was in possession of determining the HED for the large genus of cancers and correlating these values with immunotherapy response as claimed.
Although the specification discloses determining the HED of cancer patients with melanoma, NSCLC, or RCC treated with an anti-CTLA-4 or anti-PD1/PDL1 blockade therapies (particularly, Lenvatinib plus pembrolizumab with RCC patients), the claims are not limited to these diseases nor these inhibitors, and are inclusive of any cancer and any immunotherapy. Further, the claims encompass large genera of anti-CTLA-4 and PD1/PDL1 blockade therapies that are described entirely by function, without identifying correlating structure. This indicates that there are hundreds, if not thousands, of possible methods of determining HED and/or treating cancer with any immunotherapy encompassed by the claims. Thus, the claims encompass a vast genus of disease-inhibitor treatments that have the claimed functions. However, the specification provides limited guidance on the structure and steps required for maintaining the claimed function(s). Therefore, the specification does not provide adequate written description to identify the broad and variable genus of immunotherapies because, inter alia, the specification does not disclose a correlation between the necessary structure of the inhibitor and the function(s) recited in the claims; and thus, the specification does not distinguish the claimed genus from others, except by function. Further, the specification fails to provide method steps that result in determining the HED of a subject with cancer. Although the term antibody does impart some structure, the structure that is common to antibodies is generally unrelated to its specific binding function; therefore, correlation is less likely for antibodies than for other molecules. Accordingly, the specification does not define any structural features commonly possessed by the members of the genus, because while the description of an ability of the claimed substance may generically describe the molecule’s function, it does not describe the substance itself. A definition by function does not suffice to define the genus because it is only an indication of what the substance does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves the result. In addition, because the genus of substances is highly variable (i.e. each substance would necessarily have a unique structure, See MPEP 2434), the generic description of the substance is insufficient to describe the genus. Further, given the highly diverse nature of antibodies, particularly in CDRs, even one of skill in the art cannot envision the structure of an antibody by only knowing its binding characteristics. Thus, the specification does not provide substantive evidence for possession of this large and variable genus, encompassing a potentially massive number of antibodies/therapeutic agents and variants thereof claimed only be a functional characteristic(s) and/or partial structure.
A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not sufficient identifying characteristics for written description purposes, even when accompanied by a method of obtaining the agent. The specification does not adequately describe the correlation between the chemical structure and function of the genus, such as structural domains or motifs that are essential and distinguish members of the genus from those excluded. Thus, the genus of antibodies has no correlation between their structure and function.
MPEP § 2163.03(V) states:
While there is a presumption that an adequate written description of the claimed invention is present in the specification as filed, In re Wertheim, 541 F.2d 257, 262, 191 USPQ 90, 96 (CCPA 1976), a question as to whether a specification provides an adequate written description may arise in the context of an original claim. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. “Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. “Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Applicant has not shown possession of a representative number of species of treating cancers by determining the HED and administering any immunotherapy. The disclosure of only one or two species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”) (MPEP 2163).
The instant claims do not fully describe the structure of the immunotherapy/inhibitor therapy to achieve the required function. Accordingly, the specification also does not provide adequate written description to identify the broad genus of immunotherapies, claimed only by a function characteristic(s) and not structures per se, because inter alia, it does not describe a sufficient number and/or a sufficient variety of representative species to reflect the breadth and variation within the claimed genus. Consequently, based on the lack of information within the specification, there is evidence that a representative number and a representative variety of the numerous immunotherapies had not yet been identified and thus, the specification represents little more than a wish for possession. Therefore, one of skill in the art would not conclude that Applicant was in possession of the broad and highly variable genus of immunotherapies claimed only by a partial structure and functional characteristic(s). Thus the immunotherapies described by the instant claims encompasses an overly broad genus and the functional outcome.
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), it is noted that to show invention, a patentee must convey in its disclosure that is “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358). Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361). Most significant to the present case, the Court held that “knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies” (Amgen at 1361). The idea that written description of an antibody can be satisfied by the disclosure of a newly-characterized antigen “flouts basic legal principles of the written description requirement” as it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen... And Congress has not created a special written description requirement for antibodies” (Amgen at page 1362).
Abbvie v. Centocor (Fed. Cir. 2014) is also relevant to the instant claims. In Abbvie, the Court held that a disclosure of many different antibodies was not enough to support the genus of all neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support especially in technology fields that are highly unpredictable where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus.
The instant case has many similarities to AbbVie above. First, the claims clearly attempt to define the genus of immunotherapies by the functions of inhibiting immune checkpoints. Additionally, the claims attempt to define the genus of immunotherapies by the functions of blocking PD-1/PD-L1 or CTLA-4. As noted by AbbVie above, functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description. Second, there is no information in the specification based upon which one of skill in the art would conclude that the disclosed species for which applicant has identified as having the recited functions would be representative of the entire genus. The specification discloses no structure to correlate with the function. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim.
Furthermore, regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods. Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116.)
Further, the skilled artisan cannot envision the detailed chemical structure of the encompassed immunotherapies, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: ... To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (“ [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.”). Thus, an applicant complies with the written description requirement “by describing the invention, with all its claimed limitations, not that which makes it obvious,” and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention.” Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
Regarding the encompassed immunotherapies that are antibodies, the functional characteristics of antibodies (including binding specificity and affinity are dictated on their structure. Amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. For example, Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28 at 416; previously submitted in the Office Action mailed 07/14/2025) teaches that, “ … Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site.” The art shows an unpredictable effect when making single versus multiple changes to any given CDR. For example, Brown et al. (J Immunol. 1996 May;156(9):3285-91 at 3290 and Tables 1 and 2; previously submitted in the Office Action mailed 07/14/2025), describes how the VH CDR2 of a particular antibody was generally tolerant of single amino acid changes, however the antibody lost binding upon introduction of two amino changes in the same region.
The claims encompass an extremely large number of possible antibodies and therapeutic agents that have specific required functions. In the instant application, neither the art nor the specification provides a sufficient representative number of antibodies/therapeutic agents or a sufficient structure-function correlation to meet the written description requirements.
Regarding the encompassed immunotherapies that are proteins and peptides, protein chemistry is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number or location of mutation will have on a protein (such as TNF or a cytokine) as taught by Skolnick et al. (Trends Biotechnol. 2000 Jan;18(1):34-9; previously submitted in the Office Action mailed 07/14/2025), sequence-based methods for predicting protein function are inadequate because of the multifunctional nature of proteins (see e.g. abstract). Further, just knowing the structure of the protein is also insufficient for prediction of functional sites (see e.g. abstract). Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cell (see e.g. page 34, right column). Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works (see e.g. page 34, right column).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990; previously submitted in the Office Action mailed 07/14/2025) who teach that replacement of a single lysine residue at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988; previously submitted in the Office Action mailed 07/14/2025) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Further, Miosge (Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):E5189-98; previously submitted in the Office Action mailed 07/14/2025) teach that Short of mutational studies of all possible amino acid substitutions for a protein, coupled with comprehensive functional assays, the sheer number and diversity of missense mutations that are possible for proteins means that their functional importance must presently be addressed primarily by computational inference (see e.g. page E5189, left column). However, in a study examining some of these methods, Miosge shows that there is potential for incorrect calling of mutations (see e.g. page E5196, left column, top paragraph). The authors conclude that the discordance between predicted and actual effect of missense mutations creates the potential for many false conclusions in clinical settings where sequencing is performed to detect disease-causing mutations (see e.g. page E5195, right column, last paragraph). The findings in their study show underscore the importance of interpreting variation by direct experimental measurement of the consequences of a candidate mutation, using as sensitive and specific an assay as possible (see e.g. page E5197, left column, top paragraph). Additionally, Bork (Genome Research, 2000,10:398-400; previously submitted in the Office Action mailed 07/14/2025) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
One key issue is the prediction of protein function based on sequence similarity, which could be one way to identify the functional proteins that are useful in the instant claims. Kulmanov et al (Bioinformatics, 34(4), 2018, 660–668; previously submitted in the Office Action mailed 07/14/2025), teach that there are key challenges for protein function prediction methods (see e.g. page 661, left column). These challenges arise from the difficulty identifying and accounting for the complex relationship between protein sequence structure and function (see e.g. page 661, left column). Despite significant progress in the past years in protein structure prediction, it still requires large efforts to predict protein structure with sufficient quality to be useful in function prediction (see e.g. page 661, left column). Another challenge is that proteins do not function in isolation. In particular higher level physiological functions that go beyond simple molecular interactions will require other proteins and cannot usually be predicted by considering a single protein in isolation (see e.g. page 661, left column). Due to these challenges it is not obvious what kinds of features should be used to predict the functions of a protein and whether they can be generated efficiently for a large number of proteins, such as the vast genus of proteins and peptides that may be encompassed by the instant claims (see e.g. page 661, left column).
The state of the art regarding the structure-function correlation cannot be relied upon because functional characteristics of any peptide/protein are determined by its structure as evidenced by Greenspan et al. 1999 (Defining epitopes: It’s not as easy as it seems; Nature Biotechnology, 17:936-937; previously submitted in the Office Action mailed 07/14/2025). Greenspan et al. teach that as little as one substitution of an amino acid (e.g. alanine) in a sequence results in unpredictable changes in the 3-dimenstional structure of the new peptide sequence which, in turn, results in changes in the functional activity such as binding affinity of the peptide sequence (page 936, 1st column). Greenspan et al. teach that contribution of each residue (i.e. each amino acid) cannot be estimated with any confidence if the replacement affects the properties of the free form of the molecule (page 936, 3rd column).
Given not only the teachings of Skolnick et al., Lazar et al., Burgess et al., and Greenspan et al., but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed immunotherapies could not be predicted based on sequence identity. Clearly, it could not be predicted that a polypeptide or a variant that shares only partial homology with a disclosed protein or that is a fragment of a given SEQ ID NO. will function in a given manner.
Further, Examiner recognizes that HED is inherent to the patient, and generally using a patient’s germline sequence as the reference instead of the standard human reference (see McCoach and Bivona, J Thorac Dis 2018;10(3):1248-1252); however, Applicant’s invention involves the usage of immunotherapies in a large genus of cancers. It cannot be assumed that every anti-PD-1, anti-PD-L1, and/or anti-CTLA-4 antibody and cancer combination would produce therapeutic efficacy for any given drug. Cancers are highly heterogeneous at both the molecular and clinical level. Additionally, it is known in the art that cancer cells arising from different tissues differ in etiology and response to treatment. Heppner et al. (Cancer Metastasis Review 2:5-23; 1983) discuss the heterogeneity of tumors from different tissues, as well as the same tissue. A key point made by Heppner et al. is that tumor heterogeneity contributes greatly to the sensitivity of tumors to drugs. Heppner et al. teach that as a tumor progresses to a metastatic phenotype, the susceptibility to a particular treatment can differ, and as such, makes predicting the responsiveness to treatment difficult.
Negrao et al (Journal of Thoracic Oncology (2019) Vol. 14 No. 6: 1021-1031) found that PD-L1 expression, tumor mutational burden, and cancer gene mutations are stronger predictors of benefit from immune checkpoint blockade than HLA class I genotype in NSCLC (see title). Negrao et al found that HLA class I genotype is not correlated with survival in advanced NSCLC treated with immune checkpoint blockade suggesting that the impact of HLA class I diversity may be disease specific (see Abstract). Further, Negrao et al found that HLA class I zygosity is more relevant in melanoma than in NSCLC (see pg. 1029, left col.), as there were no statistically significant differences between the HLA-A, HLA-B, and HLAC-C homozygous groups and their corresponding heterozygous groups in NSCLC patients (see pg. 1028, left col.). Decreased expression of HLA class I has been associated with acquired resistance to immune checkpoint blockades in advanced NSCLC, and HLA class I mutations and loss of heterozygosity have been correlated with tumor immune evasion (see pg. 1029, right col.). Thus, the art teaches that the effectiveness of an immune checkpoint blockade is cancer specific and not based on the HLA-I genotype of the patient.
The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function (see MPEP 2163). A patent specification must set forth enough detail to allow a person of ordinary skill in the art to understand what is claimed and to recognize that the inventor invented what is claimed. In the case of DNA or proteins, an adequate written description requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention (see Lilly, 119 F.3d at 1566 (quoting Fiers, 984 F.2d 15 1171 ). Because the specification does not describe the amino acid sequences nor any core structures for potentially numerous different antibody amino acid sequences which would have the recited dissociation constant, one of skill in the art would reasonably conclude that applicant was not in possession of the claimed genus of all immunotherapies.
A key role played by the written description requirement is to prevent “attempt[s] to preempt the future before it has arrived.” Ariad at 1353, (quoting Fiers v. Revel, 984 F.2d at 1171). Upholding a patent drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of antibodies.
While “examples explicitly covering the full scope of the claim language” typically will not be required, a sufficient number of representative species must be included to “demonstrate that the patentee possessed the full scope of the [claimed] invention.” Lizard tech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724,1732 (Fed. Cir. 2005).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the claimed immunotherapies. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features (see, Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916,927, 69 USPQ2d 1886, 1895 (Fed. Cir. 2004); accord Ex Parte Kubin, 2007-0819, BPAI 31 May 2007, opinion at p. 16, paragraph 1). The specification does not clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed (see Vas-Cath at page 1116).
Without an adequate structural description of the claimed components and descriptive support on how to put them together, one of ordinary skill in the art would not be reasonably apprised that Applicant was in possession of the genus of recombinant proteins as 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 (see page 1115).
Applicant’s Arguments
Applicant requests that the written description rejection be reconsidered and withdrawn (see pages 8-15 of the Remarks filed 06/22/2026).
Applicant argues that the amended claims identify a well-defined structural class, not a functional outcome. Specifically, it defines the immunotherapies in terms of function class as well as by molecular structure, namely an antibody or binding fragment thereof. The amended claims no longer encompass small molecule therapeutics, nucleic acid-based therapeutics, aptamers, and other non-antibody modalities that the Examiner cited as sources of structural unpredictability… The specification’s working examples employ antibody-based immunotherapies, including ipilimumab (anti-CTLA-4 monoclonal antibody), pembrolizumab (anti-PD-1 monoclonal antibody), and nivolumab (anti-PD-1 monoclonal antibody). Amended claim 12 identifies seven specific immunotherapy agents, every one of which is a monoclonal antibody or binding fragment thereof. The specification thus provides not merely a single species, but numerous antibody species within the genus of “antibody or binding fragment thereof” that function as checkpoint inhibitor immunotherapies. The rejection is misplaced with respect to the statement that the antibody CDR structures are diverse and unpredictable. The Office Action draws from Amgen and AbbVie, both of which involved claims to the antibodies themselves, claims that were directed to encompassing every antibody capable of performing a specific function. The Federal Circuit's decision was concerned that the patentees were attempting to preempt future antibody development by claiming an unbound genus of structurally diverse antibodies by characteristics alone… Furthermore, the present claims are fundamentally different than Amgen, AbbVie, Juno, and In re Xencor. They are claims to a method, specifically, methods of determining HED by quantifying Grantham distance across HLA-A, HLA-B, and HLA-C loci and using that determination to guide cancer immunotherapy decisions. The antibody is not the point of novelty; it is a downstream tool employed in the final step of the inventive methods. The inventive contribution, measuring Grantham distance across three HLA-I loci, deriving mean HED, and comparing to a population-specific cancer average, is described in comprehensive detail and is not subject to any structural unpredictability concern… Further, the present amendment addresses the Examiner's concern that there are "thousands of possible immunotherapies." The present amendment further defines these therapies in terms of a monoclonal antibody or binding fragment thereof used in the context of the specific HED-determination method, the practical scope is the known checkpoint inhibitor monoclonal antibodies and their binding fragments-a genus whose members were fully identified, structurally characterized, and commercially available. This is precisely the situation Capon addressed: known components combined in a novel way to achieve a novel result, where the written description requirement is satisfied by identifying those components and demonstrating the novel combination.
Applicant argues that HED is a germline property of the patient, not a cancer-specific biomarker. The Examiner’s cancer genus objection implicitly treats HED as though it were a tumor-derived biomarker whose relevance must be independently validated in each cancer type. This fundamentally mischaracterizes the nature of HED… The HED reflects the physicochemical divergence between the patient’s inherited, germline HLA-A, HLA-B, and HLA-C alleles, as measured by the Grantham distance. HED does not vary with cancer type because it is determined entirely by the patient’s inherited, germline alleles, not by tumor-specific features such as mutational burden, histology, or tumor environment… Because the HED method measures a patient’s germline immune capacity, not a tumor-derived feature, there is no legal basis for requiring separate experimental validation in every cancer type. The method steps are identical regardless of cancer type: sequence the patient’s HLA-A, HLA-B, and HLA-C genes, compute a Grantham distance, derive mean HED, and compare the population average. The cancer type affects only which population comparator is used, not the fundamental operability of the method.
Applicant argues that the specification provides working examples across three diverse cancer types, demonstrating possession of the cancer genus. The examples encompass three different cancer types and two different classes of checkpoint inhibitors (anti-CTLA-4 and anti-PD-1). The specification further demonstrates that in a combined analysis of all four initial cohorts, an increase in mean HED corresponded to improved overall survival, and clinical response to immunotherapy was associated with high mean HED whether considering all patients or only fully heterozygous patients. Critically, the effect of mean HED on survival was shown to be independent of tumor mutational burden (TMB) and other relevant genomic and clinical variables, confirming that HED operates through a mechanism distinct from tumor-intrinsic features.
Applicant argues that the three exemplified cancer types are representative of the genus because the underlying mechanism is cancer-agnostic. The written description requirement does not demand Applicant to exemplify every species within a claimed genus. The Federal Circuit has repeatedly held that a sufficient number of representative species must be disclosed to demonstrate that the inventor possessed the full scope of the claimed invention… Here, the three exemplified cancer types, melanoma, NSCLC, and RCC, are representative of the cancer genus for several reasons. First, these three cancers are biologically diverse. Melanoma is a skin cancer arising from melanocytes, NSCLC is a lung epithelial malignancy, and RCC is a kidney cancer. They differ in tissue of origin, mutational landscape, tumor microenvironment composition, and clinical behavior. Second, the mechanistic basis for the HED effect, that broader immunopeptidome diversity leading to enhanced T-cell neoantigen recognition, is not dependent on cancer type. All cancers that respond to immune checkpoint blockade do so through a common pathway: tumor-derived neoantigens are presented by HLA-I molecules on a cell surface, which are recognized by CD8+ T cells, and targeted for killing by the patient's T cells. Higher HED increases the breadth of the neoantigen repertoire that can be presented, enhancing this pathway irrespective of the cancer. A person of ordinary skill in immunology would have understood, at the time of filing, that this mechanism applies to any cancer treated with checkpoint inhibitor immunotherapy.
Applicant argues that the authority cited in the rejection are not controlling. The cases upon which the Examiner relies, Rochester, Amgen, AbbVie, and Ariad, all involved claims in which the variable element of the genus (the compound or antibody) was the core of the invention, and structural variation within that genus was unpredictable. In Rochester, the compound was the essential operative element. In Ariad, the compound, an NF-kB inhibitor was also the essential operative element and was claimed without any description of its structure. In Amgen and AbbVie, the antibody structure dictated the claimed function. In each case, the court determined that the applicant had not described enough species to demonstrate possession of the structurally diverse genus, because each new species within the genus required a different (and unpredictable) molecular structure to achieve the claimed function. The present claims present a fundamentally different situation. The "variable" element in the claims, the cancer type, does not alter the method steps, does not require a different therapeutic agent, and does not introduce structural unpredictability. The method of determining HED by quantifying Grantham distance across HLA-A, HLA-B, and HLA-C is performed identically regardless of whether the patient has melanoma, NSCLC, RCC, or any other malignancy. The amended claims recite the same specific immunotherapies (atezolizumab, avelumab, durvalumab, ipilimumab, nivolumab, pembrolizumab, or tremelimumab) regardless of cancer type. The only element that changes with cancer type is the comparator population used to determine the average HED, a straightforward statistical calculation that does not involve structural unpredictability and one that is a routine statistical determination that any person of ordinary skill could calculate from available data for any cancer patient population. The Amgen/AbbVie/Rochester framework, which requires a representative number of structurally characterized species because molecular structure is unpredictably related to function, is inapposite to a genus defined by cancer type, where the inventive method and therapeutic agents remain constant across the genus and the cancer type introduces no structural or functional unpredictability.
Lastly, Applicant argues that the specification describes more than 100 cancer types demonstrating the inventor’s possession of the full genus. The Examiner’s prior response dismissed Applicant’s argument that the specification describes more than 100 cancers, stating that “simply because the inventors believe that the claimed methods are operable with other, non-recited cancers does not make them in possession of the claimed invention.” See, Office Action at page 33. Examiner is blowing off the statement simply because there is no back up data. The specification’s disclosure, considered in its totality, demonstrates that the combination of (1) the detailed description of the HED-determination method, (2) the mechanistic explanation of why HED influences immunotherapy response through a cancer-agnostic pathway, and (3) the working examples across three biologically diverse cancer types, may be applied to (4) each of the additional cancers enumerated therein. The Rochester court's concern was that the specification provided only a "wish or plan" (quoting Regents of the Univ. of Cal. v. Eli Lilly, 119 F.3d 1559, (Fed.Cir.1997)) for obtaining the claimed invention, a screening method without any identified compound. Here, the specification provides the complete, operative invention: a fully described method (Grantham distance measurement across HLA-A, HLA-B, and HLA-C), validated across multiple representative cancer types, with a mechanistic explanation that supports generalizability. The enumeration of additional cancer types at [0104] is neither a wish nor a plan, it is a description of additional contexts in which the fully operative, validated method may be applied. This is qualitatively different from listing potential compounds that have not yet been identified. Moreover, the Noelle v. Lederman framework described in MPEP 2163 and cited by the Examiner, that "a patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated" (see, Office Action at page 18), presupposes that there is unpredictability across species. Here, there is no such unpredictability. The method measures a patient-specific germline property that is invariant across cancer types. The specification demonstrated that the method works across three diverse cancer types, and the underlying mechanism explains why it would work across the genus.
Response to Arguments
Applicant's arguments filed 06/22/2026 have been fully considered but they are not persuasive.
Examiner acknowledges the amendments to the claims to now recite “wherein the immunotherapy is a monoclonal antibody or antigen-binding components thereof”. However, the amendments do not overcome the written description requirement for the claimed immunotherapies because the claims do not sufficiently describe the immunotherapies, excluding dependent claims 12-15. Simply indicating that the immunotherapies are monoclonal antibodies or antigen-binding components does not adequately describe what the immunotherapy is. While Applicant is entitled to use functional language in the description of claimed agents, according to MPEP 2163, an invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. This matches the facts here. The claims require that the immunotherapy block PD-1, PD-L1, and/or CTLA-4, but does not provide the structure for said immunotherapy. While methods to identify the peptides with the required function may be routine in the art, the fact that any experimentation is required to figure out exactly what is encompassed necessarily means that applicant has not sufficiently described the claimed subject matter. Additionally, the present claims are not fundamentally different than Amgen, Abbvie, Juno, and In re Xencor. The immunotherapy is a fundamental part of the invention as determining HED by quantifying Grantham distance is done only after administering the immunotherapy for claim 1; thus, for the sake of claim 1, the immunotherapy is not a downstream tool. For claim 3, the immunotherapy is not only required to block PD-1, PD-L1, and/or CTLA-4 but also to treat a subject suffering from cancer. As such, the immunotherapy is one of several points of novelty in totality of the claimed inventions.
Examiner recognizes that HED is inherent to the patient, and generally using a patient’s germline sequence as the reference instead of the standard human reference (see McCoach and Bivona, J Thorac Dis 2018;10(3):1248-1252); however, Applicant’s invention involves the usage of immunotherapies in a large genus of cancers. It cannot be assumed that every anti-PD-1, anti-PD-L1, and/or anti-CTLA-4 antibody and cancer combination would produce therapeutic efficacy for any given drug. For example, Negrao et al (Journal of Thoracic Oncology (2019) Vol. 14 No. 6: 1021-1031) found that PD-L1 expression, tumor mutational burden, and cancer gene mutations are stronger predictors of benefit from immune checkpoint blockade than HLA class I genotype in NSCLC (see title). Negrao et al found that HLA class I genotype is not correlated with survival in advanced NSCLC treated with immune checkpoint blockade suggesting that the impact of HLA class I diversity may be disease specific (see Abstract). Further, Negrao et al found that HLA class I zygosity is more relevant in melanoma than in NSCLC (see pg. 1029, left col.), as there were no statistically significant differences between the HLA-A, HLA-B, and HLAC-C homozygous groups and their corresponding heterozygous groups in NSCLC patients (see pg. 1028, left col.). Decreased expression of HLA class I has been associated with acquired resistance to immune checkpoint blockades in advanced NSCLC, and HLA class I mutations and loss of heterozygosity have been correlated with tumor immune evasion (see pg. 1029, right col.). Thus, the art teaches that the effectiveness of an immune checkpoint blockade is cancer specific and not based on the HLA-I genotype of the patient. Therefore, the present claims fail to provide written description as Applicant failed to provide sufficient support that the claimed method would treat cancer or that a patient would respond to the broad genus of immunotherapies.
As stated in response B, the art teaches that the effectiveness of an immune checkpoint blockade is cancer specific and not based on the HLA-I genotype of the patient. Negrao et al found that HLA class I genotype is not correlated with survival in advanced NSCLC treated with immune checkpoint blockade suggesting that the impact of HLA class I diversity may be disease specific (see Abstract). Further, Negrao et al found that HLA class I zygosity is more relevant in melanoma than in NSCLC (see pg. 1029, left col.), as there were no statistically significant differences between the HLA-A, HLA-B, and HLAC-C homozygous groups and their corresponding heterozygous groups (see pg. 1028, left col.). Decreased expression of HLA class I has been associated with acquired resistance to immune checkpoint blockades in advanced NSCLC, and HLA class I mutations and loss of heterozygosity have been correlated with tumor immune evasion (see pg. 1029, right col.). Therefore, the present claims fail to provide written description as Applicant failed to provide sufficient support that the claimed method would treat cancer or that a patient would respond to the broad genus of immunotherapies.
Examiner acknowledges that the specification tested three cancer types, but the claims encompass more than the three disclosed. Cancers are highly heterogeneous at both the molecular and clinical level. Additionally, it is known in the art that cancer cells arising from different tissues differ in etiology and response to treatment. Heppner et al. (Cancer Metastasis Review 2:5-23; 1983) discuss the heterogeneity of tumors from different tissues, as well as the same tissue. A key point made by Heppner et al. is that tumor heterogeneity contributes greatly to the sensitivity of tumors to drugs. Heppner et al. teach that as a tumor progresses to a metastatic phenotype, the susceptibility to a particular treatment can differ, and as such, makes predicting the responsiveness to treatment difficult. Further, with respect to Applicant’s assertion that the mechanistic basis for the HED effect is not dependent on cancer type, the art above teaches that HLA class I zygosity is more relevant in melanoma than in NSCLC making it cancer-dependent. Also, it is noted that the features upon which applicant relies (i.e., the broader immunopeptidome diversity leading to enhanced T-cell neoantigen recognition) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
As stated above, the immunotherapy is a fundamental part of the invention as determining HED by quantifying Grantham distance is done only after administering the immunotherapy for claim 1; thus, for the sake of claim 1, the immunotherapy is not a downstream tool. For claim 3, the immunotherapy is not only required to block PD-1, PD-L1, and/or CTLA-4 but also to treat a subject suffering from cancer. As such, the immunotherapy is one of several points of novelty in totality of the claimed inventions. Further, both the cancer type and the immunotherapy are the “variable” elements in the claims. So taken altogether, the claims provide inadequate description of both elements and the art provides support that HLA-I genotype diversity is different for each cancer.
Merely reciting more than 100 cancer types does not sufficiently provide support that Applicant was in possession of the claimed invention. As stated above, the art teaches that HLA class I genotype is not correlated with survival in advanced NSCLC treated with immune checkpoint blockade suggesting that the impact of HLA class I diversity may be disease specific. The art also teaches that tumor heterogeneity contributes greatly to the sensitivity of tumors to drugs and that as a tumor progresses to a metastatic phenotype, the susceptibility to a particular treatment can differ, and as such, makes predicting the responsiveness to treatment difficult. As indicated in MPEP 2163, an adequate written description of the invention may be shown by any description of sufficient, relevant, identifying characteristics so long as a person skilled in the art would recognize that the inventor had possession of the claimed invention. See, e.g., Purdue Pharma L.P. v. Faulding Inc., 230 F.3d 1320, 1323, 56 USPQ2d 1481, 1483 (Fed. Cir. 2000). Here, the unpredictability of the treatment of specific types of cancers, which requires selection of specific therapeutic agents, means that merely listing cancer types would not be sufficient to demonstrate that Applicant was in possession of the claimed invention, without more specific description of the encompassed methods. Naming cancer types is not adequate to adequately describe the specific elements necessary to perform the treatment steps to accomplish the required functions of the method. Applicant is reminded that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion”.
As such, the written description rejection is maintained.
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 2, 22, and 23 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. The claims recite a method comprising steps of: sequencing an HLA-A gene, an HLA-B gene, and an HLA-C in a subject suffering from cancer who has received a prior immunotherapy; determining an HED of the subject by quantifying the sequence divergence between an HLA-A gene, an HLA-B gene, and an HLA-C gene through measurement of the Grantham distance; and identifying the subject as a candidate for treatment with an immunotherapy when the HED of the subject is above an average HED of a population of subjects suffering from the cancer; wherein the immunotherapy is a programmed cell death protein 1 (PD-1) blockade therapy, a programmed cell death protein ligand 1 (PD-L1) blockade therapy, and/or a cytotoxic T lymphocyte-associated protein 4 (CTLA-4) blockade therapy; wherein the immunotherapy is a monoclonal antibody or antigen-binding component thereof (see claim 2).
This judicial exception is not integrated into a practical application because the claims are directed to a method of using a naturally occurring correlation, but the gathering steps required to use the correlation do not add a meaningful limitation to the method as they are insignificant extra-solution activity. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements, which are recited at a high level of generality, provide conventional assays and samples that do not add meaningful limits to practicing the law of nature and abstract idea.
Step 1: The claims are directed to the statutory category of a process.
Step 2A, prong one: Evaluate Whether the Claim Recites a Judicial Exception
The instant claims recite a law of nature. The claims recite determining whether a subject suffering from cancer has a high HED will respond to immunotherapy. This type of correlation is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court. See Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576, 589-91, 106 USPQ2d 1972, 1978-79 (2013) and Ariosa Diagnostics, Inc. v. Sequenom, 788 F.3d 1371, 1373, 115 USPQ2d 1152, 1153 (Fed. Cir. 2015).
The instant claims recite abstract ideas. The claims recite a step of “determining” or “identifying” HED by quantifying the sequence divergence between HLA class I alleles through measurement of the Grantham distance. The broadest reasonable interpretation of the “determining” or “identifying” step is that it may be accomplished by mental processes. For example, one may “determine” the response of a cancer subject by looking at a laboratory report comprising the profiles of HED values of one subpopulation of cancer patients and thinking about whether the profiles are higher than another subpopulation.
Step 2A, prong two: Evaluate Whether the Judicial Exception Is Integrated Into a Practical Application
The claims do NOT recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). For example, the claims do not practically apply the judicial exception by including one or more additional elements that the courts have stated integrate the exception into a practical application:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field;
An additional element that applies or uses a judicial exception to affect a particular treatment or prophylaxis for a disease or medical condition;
An additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
An additional element effects a transformation or reduction of a particular article to a different state or thing; and
An additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception.
Claim 2 recites a method comprising steps of: sequencing an HLA-A gene, an HLA-B gene, and an HLA-C in a subject suffering from cancer who has received a prior immunotherapy; determining an HED of the subject by quantifying the sequence divergence between an HLA-A gene, an HLA-B gene, and an HLA-C gene through measurement of the Grantham distance; and identifying the subject as a candidate for treatment with an immunotherapy when the HED of the subject is above an average HED of a population of subjects suffering from the cancer; wherein the immunotherapy is a programmed cell death protein 1 (PD-1) blockade therapy, a programmed cell death protein ligand 1 (PD-L1) blockade therapy, and/or a cytotoxic T lymphocyte-associated protein 4 (CTLA-4) blockade therapy; wherein the immunotherapy is a monoclonal antibody or antigen-binding component thereof. These determining and identifying steps are not particular and is instead merely instructions to apply the judicial exceptions in a generic way. These determining and identifying steps do not integrate the judicial exceptions into a practical application.
These steps are NOT considered to integrate the judicial exceptions into a practical application because they merely add insignificant extra-solution activity (data gathering) to the judicial exception. See MPEP 2106.05(g).
Step 2B: Evaluate Whether the Claim Provides an Inventive Concept
In addition to the judicial exceptions, the claims recite steps of determining the HED of a cancer subject. These steps do not amount to significantly more because they simply append well understood, routine, and conventional activities previously known in the art, specified at a high level of generality, to the judicial exceptions.
The steps are recited at a high level of generality. Determining HED in biological samples from a cancer subject merely instructs a scientist to use any of the known detection techniques. The claims do not require the use of any particular non-conventional reagents. When recited at this high level of generality, there is no meaningful limitations that distinguish these steps from well understood, routine, and conventional activities engaged in by scientists prior to Applicants invention and at the time the application was filed.
Nothing is added by identifying the techniques to be used in the detection steps (i.e., measurement of the Grantham distance) because these were the well-understood, routine, and conventional techniques that a scientist would have thought of when instructed to determine the HED of a cancer subject.
Further, it is noted that the courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. V. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014)
For the reasons set forth above the claims are not directed to patent eligible subject matter.
Applicant’s Arguments
Applicant respectfully disagrees with the 101 rejection (see pages 16-21 of the Remarks filed on 06/22/2026).
Applicant argues that under CellzDirect, the present claims are directed to a new and useful laboratory technique, not to a law of nature. The Examiner characterizes the claims as directed to "a method of using a naturally occurring correlation" (see, Office Action at page 34), namely, the correlation between high HED and immunotherapy response, and concludes that "the gathering steps required to use the correlation do not add a meaningful limitation." Id. This analysis improperly disaggregates the claims into their individual components and then dismisses each in isolation, precisely the approach the Federal Circuit rejected in CellzDirect… Here, the claims are not directed to the mere observation that HED correlates with immunotherapy response. They are directed to a multi-step, technically specific method of: (1) sequencing the HLA-A, HLA-B, and HLA-C genes of a cancer subject who has received a prior immunotherapy; (2) determining the subject's HED by quantifying the sequence divergence between those three loci through measurement of the Grantham distance, a physicochemical metric integrating amino acid composition, polarity, and molecular volume; and (3) identifying the subject as a candidate for further immunotherapy treatment (claim 2) or determining whether the subject will respond to immunotherapy (claim 4) when the HED exceeds an average HED of a population of subjects with the same cancer. Claims 22 and 23 further specify that the HED is determined as the mean evolutionary divergence between all of the HLA-A, HLA-B, and HLA-C genes.
Applicant argues that the claims recite a new process, not merely “data gathering” appended to a natural correlation. The Examiner dismisses the sequencing and Grantham distance calculation steps as "insignificant extra-solution activity" and "well-understood, routine, and conventional techniques." See, Office Action at pages 34-36. This analysis fails under CellzDirect for several reasons. First, the CellzDirect court expressly rejected the argument that method claims exploiting a natural phenomenon are ineligible simply because the individual technique steps were known… Second, the CellzDirect court distinguished between claims that merely observe a natural phenomenon and those that apply it… Third, the characterization of the "determining" and "identifying" steps as mental processes is inconsistent with CellzDirect.
Applicant argues that the claims satisfy CellzDirect's practical application requirement. The CellzDirect court identified a key distinction between claims that are "directed to" a law of nature and claims that "apply" a law of nature through a "new and useful" process… Likewise, the presently claimed methods produce a tangible and useful result, namely a clinical determination that a specific cancer patient is or is not a candidate for a specifically targeted immunotherapy treatment. This is not a mere abstract observation… While claims 2 and 4 do not themselves recite an administration step, they produce a particularized treatment determination for a specific patient population, subjects suffering from cancer who have received a prior immunotherapy, that directly guides therapeutic decision-making. The Examiner states that the claims merely result in "identifying a subject, not treatment." See, Office Action at page 40. But the CellzDirect court held that claims need not recite a treatment step to be eligible; what matters is whether the claims achieve a "new and useful end" through a concrete process. CellzDirect, 827 F.3d at 1048. The identification of a cancer patient as a candidate for immunotherapy based on a specific, quantitative HED threshold, determined via Grantham distance measurement, is a concrete, clinically actionable result that a physician can use to guide further treatment. It is qualitatively different from merely "observing" a natural correlation or "thinking about" laboratory data. The claims produce a determination of treatment candidacy tied to a specific quantitative biomarker threshold (mean HED above the population average) for a particular patient population (cancer patients who have received prior immunotherapy). This is the very type of clinically meaningful, practical application that satisfies CellzDirect and the USPTO's guidance.
Applicant argues that the ordered combination of steps is not well-understood, routine, or conventional. Even assuming, arguendo, that the claims are directed to a judicial exception at Step 2A, they satisfy Step 2B because the ordered combination of steps constitutes an "inventive concept" under CellzDirect… Here, the ordered combination of (1) sequencing all three HLA class I loci (HLA-A, HLA- B, and HLA-C) in a cancer patient who has received prior immunotherapy, (2) computing the Grantham distance across those loci, (3) deriving a mean HED, and (4) comparing that mean HED to a population-specific average to identify the patient as an immunotherapy candidate was not well-understood, routine, or conventional. The Examiner cites Mayo, Genetic Techs., Ariosa, Sequenom, and University of Utah Research Foundation for the proposition that sequencing, detecting DNA, and analyzing allelic variants are routine. See, Office Action at page 37. But in CellzDirect, while the court acknowledged that the claimed steps were individually known techniques, it still held that Appellant's novel combination constituted an inventive concept. The relevant inquiry is not whether any individual step was known, but whether the particular ordered combination was routine. In CellzDirect, it plainly was not. Here too, no prior art of record shows that combining HLA-I sequencing with Grantham distance calculation, mean HED determination, and population- level HED comparison to guide cancer immunotherapy decisions. Moreover, the Federal Circuit has held that whether claim elements are "well-understood, routine and conventional to a skilled artisan in the relevant field is a question of fact," and that these facts "must be proven by clear and convincing evidence," not mere Examiner assertion. Berkheimer v. HP Inc., 881 F.3d 1360, 1368 (Fed. Cir. 2018). The Examiner has not proffered any evidence record establishing that the claimed combination of steps for HED-based cancer immunotherapy candidacy determination was routine or conventional at the time of filing. The reliance on generalized statements about HLA typing and biomarker detection does not meet this evidentiary standard. The specification discloses that the method was validated across multiple independent cancer cohorts, melanoma patients treated with anti-CTLA-4, NSCLC patients treated with anti-PD-1, metastatic melanoma patients treated with anti-PD-1, and RCC patients treated with Lenvatinib plus pembrolizumab, representing a novel contribution to the field of precision oncology, not the application of routine techniques.
Response to Arguments
Applicant's arguments filed 06/22/2026 have been fully considered but they are not persuasive.
First, Examiner acknowledges the amendments to the claims and has amended the rejection to no longer include claim 4. However, Examiner respectfully disagrees with Applicant’s assertion that the present claims are directed to a new and useful laboratory technique, and not a law of nature similar to CellzDirect. The issue with CellzDirect was whether the ‘929 patent claims are directed to a patent-ineligible concept under 35 USC 101. The ‘929 patent describes a method of hepatocyte cryopreservation comprising collecting resilient hepatocytes by subjecting a pool of previously frozen and thawed hepatocytes from multiple donors to density gradient fractionation – which separates viable from non-viable hepatocytes – and then refreezing the viable cells. This process yields a much higher proportion of viable hepatocytes after the second thaw, allowing researchers to more easily prepare and pool samples from multiple donors. The facts of CellzDirect does not compare with the present invention because the present invention is not improving an existing technological process. The art teaches that PD-L1 expression, tumor mutational burden, and cancer gene mutations are stronger predictors of benefit from immune checkpoint blockade than HLA class I genotype in NSCLC (see Negrao et al). Therefore, determining one’s HLA-I diversity is not only not useful, it’s also not a new technique in identifying a subject as a candidate for treatment with an immunotherapy.
The present invention is indicating that there is a correlation between the HED of a subject and the subject’s eligibility for treatment. While the claims indicate that the HED is quantified by measuring the Grantham distance, this does not add a meaningful limitation to the method because the art teaches that other factors are stronger predictors than HLA-I genotype for determining immunotherapy benefit. Therefore, quantifying the HED (no matter the method of measuring) does not make it useful or improving an existing technique because it’s not a good indicator for therapy effectiveness. This is even supported by the post-filing literature that Applicant cites. Schetelig teaches that there was no significant correlations of the Grantham distance with the risk of symptomatic infections, severe respiratory infections, or respiratory hospitalizations (see pages 7 and 8). Additionally, the art cited by Applicant do not determine the HED of a subject to then identify whether that subject is a candidate for treatment. The Arora art, as Applicant states in their argument, found that the Grantham distance was a useful proxy for the overlap in binding properties. As such, Applicant referencing CellzDirect, Aurora, and Schetelig are not good comparisons for the present invention because the outcomes for each are different.
Examiner respectfully disagrees with Applicant’s assertion that the presently claimed methods produce a tangible and useful result similar to CellzDirect. With CellzDirect, the tangible result was viable hepatocytes after the second thaw that allow researchers to more easily prepare and pool samples from multiple donors. That is something physical that researchers can utilize. Identifying a subject as a candidate for treatment is not a tangible result. The broadest reasonable interpretation of the “determining” or “identifying” step is that it may be accomplished by mental processes/observation. This type of correlation is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court. See Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576, 589-91, 106 USPQ2d 1972, 1978-79 (2013) and Ariosa Diagnostics, Inc. v. Sequenom, 788 F.3d 1371, 1373, 115 USPQ2d 1152, 1153 (Fed. Cir. 2015). For example, one may “determine” the response of a cancer subject by looking at a laboratory report comprising the profiles of HED values of one subpopulation of cancer patients and thinking about whether the profiles are higher than another subpopulation. The claimed method is not providing an administering step wherein the candidate is then provided treatment.
Again, Applicant is comparing the facts of CellzDirect with the present invention when they do not correlate. CellzDirect is drawn to a tangible and useful laboratory technique. The present claims are not only intangible, there is prior art that indicates that the parameter being measured (i.e., HED) is not useful in determining the effectiveness of immunotherapy in cancer patients. Nothing is added by identifying the techniques to be used in the detection steps (i.e., measurement of the Grantham distance) because these were well-understood, routine, and conventional techniques that a scientist would have thought of when instructed to determine the HED of a cancer subject. Even more, the steps of sequencing genes and then determining a quantifiable value utilizing said sequenced genes to identify the eligibility of a subject based on the quantifiable value are well-understood, routine, and conventional techniques.
As such, the 101 rejection is maintained.
Conclusion
Claims 1-4, 7-9, 17, 18, and 22-24 are rejected.
Claims 12-15 are objected to as being dependent upon a rejected base claim.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANAYA L MIDDLETON whose telephone number is (571)270-5479. The examiner can normally be reached M-F 9:30AM - 6PM with flex.
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/DANAYA L MIDDLETON/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674
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