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 11/14/2025, are acknowledged.
Claims 5, 6, and 19-21 are canceled.
Claims 1-4 and 7-18 are amended.
Claims 22-24 are new.
Claims 1-4, 7-18, and 22-24 are pending.
As such, claims 1-4, 7-18, and 22-24 are pending examination and currently under consideration for patentability under 37 CFR 1.104.
DETAILED ACTION
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/14/2025 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825. This application contains a “Sequence Listing” as a PDF file (37 CFR 1.821(c)(2)) or as physical sheets of paper (37 CFR 1.821(c)(3)). A copy of the "Sequence Listing" in computer readable form (CRF) has been submitted; however, the content of the CRF does not comply with one or more of the requirements of 37 CFR 1.822 through 1.824, as indicated in the "Error Report" that indicates the "Sequence Listing" could not be accepted. Refer to attachment or document "Computer Readable Form (CRF) for Sequence Listing – Defective" dated 11/17/2025.
Required response – Applicant must provide:
A replacement "Sequence Listing" part of the disclosure, as described above in item 1); together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the replacement "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter and
An amendment to the specification to remove the “Sequence Listing previously submitted as a PDF file (37 CFR 1.821(c)(2)) or as physical sheets of paper (37 CFR 1.821(c)(3))
If the replacement "Sequence Listing" part of the disclosure is submitted according to item 1) c) or d) above, Applicant must also provide:
A CRF in accordance with 1.821(e)(1) or 1.821(e)(2) as required by 37 CFR 1.825(b)(6)(ii); and
Statement according to item 2) a) or b) above.
Withdrawn Objections
The drawings objections are withdrawn in part. Issues regarding minor informalities have been addressed through amendments to the drawings on 11/14/2025. Specifically, the following objections are withdrawn:
Figures 5a to 5c, 6a to 6d, 7a to 7c, 8a to 8c, 14a-14b, 15a-15e, and 16a-16e descriptions reciting colors;
Figure 8c shows “p = 0.61” whereas the description recites “ p = 0.51”;
Figure 11b shows “p = 0.0001” whereas the description recites “p = 0.001”;
Figure 11i shows “p < 0.0001” whereas the description recites “p = 0.79”; and,
The specification references a “Fig. 15f” (e.g., see [0026]); however, this figure is not disclosed in the drawings.
The specification objections are withdrawn. Issues regarding minor informalities, hyperlinks, and trademarks/names have been sufficiently addressed through amendments to the specification on 11/14/2025.
The claim objections are withdrawn. Issues regarding minor informalities have been sufficiently addressed through amendments to the claims filed on 11/14/2025.
Withdrawn Rejections
Applicant’s arguments, see page 10, filed 11/14/2025, with respect to claims 10-16 rejected under 35 USC 112(d) as allegedly being of improper dependent form have been fully considered and are persuasive. The issue regarding improper dependent subject matter have been sufficiently addressed through amendments to the claims. As such, the rejection under 35 USC 112(d) is withdrawn.
Applicant’s arguments, see pages 10-12, filed 11/14/2025, with respect to claims 1-18 rejected under 35 USC 112(b) as allegedly being indefinite have been fully considered and are persuasive. The issue regarding the claims comprising indefinite language have been sufficiently addressed through amendments to the claims. Further, Examiner acknowledges that claims 5, 6, and 19-21 are canceled thus rendering the rejection moot. As such, the rejection under 35 USC 112(b) is withdrawn.
Applicant’s arguments, see pages 13 and 14, filed 11/14/2025, with respect to claims 2 and 3 rejected under 35 USC 112(a) as allegedly failing to comply with the enablement requirement have been fully considered and are persuasive. The issue regarding the claims failing to disclose an enabling invention have been sufficiently addressed through amendments to the claims. As such, the rejection under 35 USC 112(a) is withdrawn.
Applicant’s remarks, see page 17, filed 11/14/2025, with respect to claims 1-5, 7-15, and 17-18 rejected under 35 USC 102 as allegedly anticipated by Chowell et al have been fully considered and are persuasive. Examiner acknowledges that claim 5 is canceled, thus rendering the rejection moot. Further, Examiner acknowledges that claims 1-4, 7-15, and 17-18 were amended to recite “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” which is not disclosed by Chowell et al. As such, the rejection of claims 1-5, 7-15, and 17-18 under 35 USC 102 is withdrawn.
Applicant’s remarks, see pages 17-21, filed 11/14/2025, with respect to claims 1-15 and 17-18 rejected under 35 USC 103 as allegedly being unpatentable over Chowell et al in view of Pierini et al; and claims 1, 5, and 7-18 rejected under 35 USC 103 as allegedly being unpatentable over Chowell et al in view of Van Allen et al have been fully considered and are persuasive. Examiner acknowledges that claims 5 and 6 are canceled, thus rendering the rejection moot. Further, Examiner acknowledges that claims 1-4 and 7-18 were amended to recite that a subject has had prior immunotherapy and “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” which is not disclosed by the art. As such, the rejection of claims 1-18 under 35 USC 103 is withdrawn.
Applicant’s remarks, see pages 21-23, filed 11/14/2025, with respect to claims 1-5 and 7-18 rejected on the ground of non-statutory double patenting of US Patent No. 10,993,998 in view of Chowell; claims 1-18 rejected on the ground of non-statutory double patenting of US Patent No. 10,993,998 in view of Pierini; claims 1-5 and 7-18 rejected on the ground of non-statutory double patenting of US Patent No. 11,230,599 in view of Chowell; claims 1-18 rejected on the ground of non-statutory double patenting of US Patent No. 11,230,599 in view of Pierini; claims 1-5 and 7-18 provisionally rejected on the ground of non-statutory double patenting of US Application No. 17/536,715 in view of Chowell; and, claims 1-18 provisionally rejected on the ground of non-statutory double patenting of US Application No. 17/536,715 in view of Pierini have been fully considered and are persuasive. Examiner acknowledges that claim 5, 6, and 19-21 are canceled, thus rendering the rejection moot. Further, Examiner acknowledges that claims 1-4, 7-15, and 17-18 were amended to recite that a subject has had prior immunotherapy and “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” which is not disclosed by the art. As such, the (provisional) double patenting rejections are withdrawn.
Maintained Objections and Rejections
Drawings
The drawings are objected to because the specification recites “P = 0.61” for Fig. 8b; however, the drawing shows “p = 0.48”. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Applicant’s Arguments
Applicant asserts that a substitute specification is submitted herewith to amend the description of the drawings by patterns in place of color, to recite the p-values shown in the figures, and to remove the reference to FIG. 15F. Reconsideration and withdrawal of all grounds of objection are respectfully requested.
Response to Arguments
Applicant’s arguments filed 11/14/2025 have been fully considered but they are not persuasive in part. As stated above, majority of the objections regarding the drawings are withdrawn; however, Fig. 8b remains objected to because the specification was amended to recite “P = 0.61” which is different from the p-value recited in the drawing. As such, the drawing objection of Fig. 8b is maintained.
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, 7-18, 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.
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.
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.
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.
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 10 is drawn to the method of claim 1, wherein the immunotherapy is an immune checkpoint modulator.
Claim 11 is drawn to the method of claim 1, wherein the immunotherapy is an antibody agent.
Claim 12 is drawn to the method of claim 1, wherein the immunotherapy is a monoclonal antibody.
Claim 13 is drawn to the method of claim 1, wherein the immunotherapy is of a PD-1 blockade therapy and/or a PD-L1 blockade therapy.
Claim 14 is drawn to the method of claim 1, wherein the immunotherapy is CTLA-4 blockade therapies.
Claim 15 is drawn to the method of claim 1, wherein the immunotherapy is a PD-1 blockade therapy and a CTLA-4 blockade therapy.
Claim 16 is drawn to the method of claim 1, wherein the immunotherapy is selected from the group comprising of atezolizumab, avelumab, durvalumab, ipilimumab, nivolumab, pembrolizumab, or tremelimumab, and combinations therein.
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 claim 16. The specification fails to disclose that Applicant was in possession of the genus of immune checkpoint inhibitors, 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.
Regarding immunotherapies that are small molecules of a particular protein target, the prediction of binding to a target, much less the inhibitory activity, is highly unpredictable. According to Guido et al. (Curr Med Chem. 2008;15(1):37-46; previously submitted in the Office Action mailed 07/14/2025), accurately predicting the binding affinity of new drug candidates remains a major challenge in drug discovery (see page 37). There are a vast number of possible compounds that may bind any particular target, many of which have likely not been discovered. Relying on virtual screening also lends unpredictability to the art regarding identification of molecules that would be capable of the required functions of the instant claims. Guido et al. teach that there are two main complex issues with predicting activity for a small molecule: accurate structural modeling and/or correct prediction of activity (see page 40). As taught by Clark et al. (J. Med. Chem., 2014, 57 (12), pp 5023–5038; previously submitted in the Office Action mailed 07/14/2025), even when guided by structural data, developing selective structure-activity relationships has been challenging owing to the similarities of the enzymes (see page 5028). Therefore, it is impossible for one of skill in the art to predict that any particular encompassed small molecule therapeutic would function to inhibit a particular protein, especially a particular protein family member, or treat disease.
Regarding immunotherapies that are nucleic acid-based therapeutics, the efficacy of any possible DNA or RNA based therapeutic modality is highly unpredictable. This unpredictability stems from an inability to predict the effects of any particular sequence the expression or function of any target. As taught by Aagaard et al. (Advanced Drug Delivery Reviews 59 (2007) 75–86; previously submitted in the Office Action mailed 07/14/2025), the development of RNAi based therapeutics faces several challenges, including the need for controllable or moderate promoter systems and therapeutics that are efficient at low doses (see page 79), the ability of an unpredictable number of sequences to stimulate immune responses, such as type I interferon responses (see page 79), competition with cellular RNAi components (see page 83), the side effect of suppressing off targets (see page 80), and challenging delivery (see page 83). The success of antisense strategies, including anti-RNA and anti-DNA strategies are also highly unpredictable. Warzocha et al. (Leukemia and Lymphoma (1997) Vol. 24. Pp. 267-281; previously submitted in the Office Action mailed 07/14/2025) teach that the efficacy of antisense effects varies between different targeted sites of RNA molecules and three-dimensional RNA structures (see page 269), while DNA-targeting strategies have numerous problems including a restricted number of DNA sequences that can form triple helices at appropriate positions within genes and the inaccessibility of particular sequences due to histones and other proteins (see page 269). These references demonstrate that variation in RNA or DNA based therapeutics will often dramatically affect the biological activity and characteristics of the intended therapeutic. McKeague et al. (J Nucleic Acids. 2012;2012:748913. Epub 2012 Oct 24; previously submitted in the Office Action mailed 07/14/2025) teach that aptamers have particular challenges because unlike antibodies or molecular imprinted polymers, their tertiary structure is highly dependent on solution conditions and they are easily degraded in blood. Further, they have less chemical diversity than other antagonist molecules (see page 2), and have issues associated with determining the Kd measurements for a given molecule (see page 13).
Given the teachings of Aagaard et al, Warzocha et al, and McKeague et al, the claimed nucleic acid therapeutics could not be predicted based on the targets selected or similarities to the disclosed example therapeutics. Therefore, it is impossible for one of skill in the art to predict that any particular encompassed nucleic acid based therapeutic, such as oligonucleotide aptamers, RNAi molecules and antisense oligonucleotides, would function to decrease expression or function of a target gene or protein, or treat disease.
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 respectfully requests reconsideration and withdrawal of the written description rejection (see pages 11 and 12 of the Remarks filed on 11/14/2025).
Applicant asserts that claims 1 and 4 have been amended to recite that the immunotherapy is a PD-1 blockade therapy, a PD-L1 blockade therapy, and/or a CTLA-4 blockade therapy. The specification exemplifies representative blockade therapies for PD-1, PD-L1, and CTLA-4 to treat cancer. See, for example, [0091] of the specification. Applicant was in possession of the claimed invention with respect to the cancers encompassed by the claims. The specification makes clear that the inventors believe that the claimed methods are operable with other, non-recited cancers. It describes more than 100 cancers. See, [0104] of the specification. Furthermore, the treatment of these cancers by the claimed immunotherapies were well-known to those skilled in the art at the time of filing. This disclosure, coupled with experimental confirmation with melanoma, NSCLC, and RCC, would have clearly demonstrated to persons skilled in the art that Applicant was in possession of the full scope of its claimed invention.
Response to Arguments
Applicant’s arguments filed 11/14/2025 have been fully considered but they are not persuasive.
Examiner acknowledges the amendments to claims 1 and 4; however, the immunotherapies are solely described by their function (i.e., PD-1/PD-L1 and/or CTLA-4 blockade). 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 specific functionality for the immunotherapies, but neither the instant disclosure, nor the art, provide description of the corresponding structure for that functionality or a representative number of species for the agents/components. For example, the PD-1, PD-L1, and/or CTLA-4 blockade therapies are defined by its binding specificity, and by their ability to block a specific protein. In both the base claims and the dependent claims, for at least one agent/component in each claim, the claims only describe what the agent/component does, not what the agents/components are. Even when given possible sequences from which to select a fragment of a peptide that would block PD-1, PD-L1, and/or CTLA-4, the question remains about which one(s) of the encompassed peptides would actually perform the claimed function. 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.
There are thousands of possible immunotherapies encompassed by the instant claims. One of skill in the art could not immediately envisage the encompassed species in each genus from the guidance provided in the instant specification and claims. Applicant has supplied a single species of cancer-immunotherapy treatment, which comprises administering Lenvatinib and pembrolizumab to patients with RCC with high mean HED; however, the claims are not limited to this species, or even polyclonal antibodies. The claims encompass all cancers and PD-1, PD-L1, and/or CTLA-4 blockade therapies. This encompasses an extremely broad genus of peptides with a specific function, for which no correlating structure is provided. While one of skill in the art could likely screen for said peptides and antibodies, the mere fact that experimentation is necessary to identify the members of the genus indicates that proper description has not been provided.
The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 “merely by clearly describing one embodiment of the thing claimed.” LizardTech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1346, 76 USPQ2d 1731, 1733 (Fed. Cir. 2005). Describing a composition by its function alone typically will not suffice to sufficiently describe the composition. See Eli Lilly, 119 F.3 at 1568, 43 USPQ2d at 1406 (Holding that description of a gene’ s function will not enable claims to the gene “because it is only an indication of what the gene does, rather than what it is.”); see also Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991)). An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that “[w]ithout such disclosure, the claimed methods cannot be said to have been described.”).
The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself even when preparation of such an antibody would be routine and conventional. Amgen Inc., v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). 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. In the instant application, neither the art nor the specification provide a sufficient representative number of antibodies or a sufficient structure-function correlation to meet the written description requirements.
With respect to Applicant’s argument that the inventors were in possession of the claimed invention with respect to the cancers and immunotherapies encompassed by the claims, 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 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. Further, arguments relating to the isolation of an antibody with specific characteristics may be more appropriately directed to the invention' s enablement, since the method of isolating would detail how to make the invention. However, the enablement of the invention has not been rejected by the Examiner.
Regarding the disclosed species in the specification, Applicant is reminded that the species recited in paras. [0091] and [0104] of the specification are merely examples and the claims are not limited to the species described in the arguments, and instead encompass a large genus of admixtures, for which the components are not adequately described. Lastly, 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. The mere fact that experimentation is necessary to identify the members of the genus indicates that proper description has not been provided.
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, 4, and 22-23 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 (see claim 2); and, 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 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 (see claim 4).
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. Claim 4 recites 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 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. 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 requests reconsideration and withdrawal of the 101 rejection (see pages 14-17 of the Remarks filed on 11/14/2025).
Analyzed as a whole, the present claims amount to significantly more than the judicial exception. As amended, independent claims 2 and 4 recite the additional element of sequencing the HLA-A, HLA-B, and HLA-C genes of a subject who has received a prior immunotherapy, determining the subject’s HED 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 when the HED of the subject is above an average HED of a population of subjects suffering from the cancer. The amended claims recite that the subject has had the active step of receiving a prior immunotherapy. Additionally, although measuring the Grantham distance measurement was known in the art at the time the application was filed, to Applicant’s knowledge, it was not “routine” or “conventional” at least insofar as measuring HED and comparing that HED of a population of individuals for the purpose of gauging responsiveness to cancer immunotherapy. The Grantham distance measurement was used in evolutionary biology. However, at the time the application was filed, the Grantham distance of the HLA loci was used to identify selection of human pathogens. Even post-filing literature supports Applicant’s position. See, e.g., Arora et al., Mol. Biol. Evol. 37(3):639-650 (2020) (“Arora”) and Schetelig et al., Front. Immunol. 12:698193 (2021) (courtesy copies of which are submitted herewith in an Information Disclosure Statement). Arora makes this clear, stating “[p]athogen-mediated balancing selection is regarded as a key driver of host immunogenetic diversity.” Arora, Abstract at page 639. Arora concludes that: “Interestingly, after including allele-specific additive effects, which account for the allele-specific HIV-1 peptide repertoire size, the effect of HLA-B sequence divergence and predicted combined number of bound HIV-1 peptides becomes very similar. This suggests that allele divergence (here measured as Grantham distance) is a useful proxy for the overlap in binding properties [of HIV-1], that is, the redundancy in presented peptides between two HLA alleles.” Arora, at page 645, right hand column, 1st paragraph to page 646, left hand column, 1st paragraph. Even the Examiner’s cited Pierini supports this view, stating that the associations between the HLA gene divergence and certain pathogen antigens “might indicate that the exceptional sequence divergence commonly observed among alleles of a given MHC locus has evolved specifically in response to selection by pathogens that are processed through the major protein degradation and antigen-presentation pathways.” See, Pierini at page 2153, left hand column, 1st paragraph. Thus, the claims, considered as a whole, amount to significantly more than the judicial exception itself (Step 2B, yes).
The present claims are comparable to Example 29 of the 2014 Interim Guidance on Patent Subject Matter Eligibility Examples: Life Sciences, and particularly claim 3 therein… Examples: Abstract Ideas, referenced in the 2014 Interim Guidance on Patent Subject Matter Eligibility, at pages 12 (emphasis added). In the instant case, determining a subject’s HED with the Grantham distance and comparing the subject’s HED with an average of a population’s HED for the use in determining responsiveness to cancer immunotherapy was an unconventional step at the time of filing that is more than applying the correlation and a critical thinking step.
Response to Arguments
Applicant’s arguments filed 11/14/2025 have been fully considered but they are not persuasive.
Examiner acknowledges the amendments to claims 2 and 4; however, these amendments do not amount to significantly more than the judicial exception as stated by the Applicant. First, the steps of sequencing, quantifying, and identifying are well-understood, routine, and conventional techniques that a scientist would have pursued when instructed to determine the HED of a cancer subject. Specifically, as supported by Applicant, the teachings of Pierini disclose that Grantham distance measure consistently showed the strongest correlation of allele divergence between the HLA genes (see page 2147, right column). Furthermore, with respect to the “immunotherapy” recited in the claims, the claims do not recite a specific immunotherapy and thus this limitation does not add significantly more to the judicial exception.
Further, Examiner respectfully disagrees with Applicant’s assertion that the present claims are comparable to Example 29 of the 2014 Interim Guidance on Patent Subject Matter Eligibility Examples: Life Sciences (claim 3). This differs from the present claims because claim 3 of Example 29 is drawn to a method of detecting the presence of JUL-1 in a plasma sample comprising contacting the plasma sample with a porcine anti-JUL-1 antibody and detecting resultant binding between JUL-1 and the antibody. Firstly, the present claims are not directed to administering an antibody that targets the specific antigen that is being detected in a sample. Secondly, the present claims do not provide any context as to what the prior immunotherapy was, thus one would not be apprised if the prior immunotherapy impacts the HED value of the subject. Thirdly, the example of the anti-JUL-1 antibody provided a unique product that was not known in the art. In contrast, there is no novel product that is used in the instant claims, and in fact the claims rely on a technique (i.e. sequence divergence measurement) that is known in the art. Therefore, the method of the instant claims is not comparable to use of a novel antibody for measurement. Lastly, if after quantifying the HED of a subject the subject is deemed a candidate for treatment, the claims do not recite what immunotherapy would be administered. The amendments to the present claims fail to provide a correlation between the immunotherapies and the HED of the subject. Instead the measurement is directed entirely to identifying a subject, not treatment. Thus, Applicant’s comparison of the present claims to Example 29, claim 3 is not appropriate.
As such, the 101 rejections are maintained.
New Objections and Rejections Necessitated by Amendment
Claim Objections
Claims 1-4 are objected to because of the following informalities:
Claims 1-3: Every instance of “… an HLA-A gene an HLA-B gene, and an HLA-C gene…” should read “… an HLA-A gene, an HLA-B gene, and an HLA-C gene…”.
Claims 2 and 4: Every instance of “sequencing an HLA-A gene, an HLA-B gene, and an HLA-C…” should read “sequencing an HLA-A gene, an HLA-B gene, and an HLA-C gene…”.
Appropriate correction is required.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/DANAYA L MIDDLETON/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674