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 .
DETAILED ACTION
This office action is in reply to Applicant’s response of 4 August 2025. Applicant’s remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in a condition for allowance. Note: on page 11, paragraphs 2 and 3 of Applicant’s response of 4 August 2025, Applicant references “paragraph 0004]” and “paragraph 0004-0005]”, presumably within the specification. The specification as filed is detailed with page and line numbers, which Applicant appropriately used within the rest of Applicant’s response. Consistency in the manner of referencing text with the filed specification is requested.
Note: The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This action is made Non-Final.
Claim Status
Claims 1-5, 7-8, 10, 13, and 15-23 are pending. Claims 1-2, 4, 10, 13, 15-17, 19, and 21 are currently amended.
Claims 6, 9, 11-12, and 14 are canceled.
Response to Amendment
The amendment filed 4 August 2025 has been entered. Applicant’s amendments to the Specification and Claims have overcome each and every objection previously set forth in the Non-Final Office Action mailed 2 April 2025. The objections to the disclosure and claims as set forth on pages 2-3 of the Office Action of 2 April 2025 are therefore withdrawn.
Withdrawn Claim Rejections
The rejection of claims 1-5, 7-8, 10, and 12-23 under 35 U.S.C. 112(b) because rs4503084 is not a SNP has been withdrawn due to amendments curing the rejection. The further rejections of claims 1, 2, 10, 15, 16, 17, and 21 under 35 U.S.C. 112(b) have also been withdrawn due to amendments curing the rejections.
All rejections of claims 12 and 14 have been withdrawn because the cancelation of claims 12 and 14 renders the rejections moot.
The rejection of claim 21 under 35 U.S.C. Section 102 has been withdrawn based on applicant’s amendment to claim 21.
Specification
Newly Applied
The disclosure is objected to because of the following informalities:
The title of Table 31 describes it as containing data of “Positive Male Responders”, Examiner suggests this is intended to be “Positive Female Responders” based on the paragraphs after Table 31 that describe its contents.
Appropriate correction is required.
The amendment filed 4 August 2025 is objected to under 35 U.S.C. 132(a) because it introduces new matter into the disclosure. 35 U.S.C. 132(a) states that no amendment shall introduce new matter into the disclosure of the invention. The added material which is not supported by the original disclosure is as follows: the replacement of "rs4503084" with "rs4503083" on page 2 lines 21-22 and 29, page 10 line 22, page 11 lines 26-27, and page 14 line 2. Per MPEP §2163.07 II., “An amendment to correct an obvious error does not constitute new matter where one skilled in the art would not only recognize the existence of error in the specification, but also the appropriate correction. In re Oda, 443 F.2d 1200, 170 USPQ 268 (CCPA 1971)”. As both rs4503083 and rs4503084 were used in the initial disclosure, it is not clear that one of ordinary skill in the art would recognize the error in the specification and, even if they did recognize the error, that they would also recognize the appropriate correction.
Applicant is required to cancel the new matter in the reply to this Office Action.
Claim Objections
Newly Applied
Claim 1 is objected to because of the following informalities: lines 6-7 recite "mutation of least one of". This recitation is interpreted as intending to mean "mutation of at least one of".
Claim 2 is objected to because of the following informalities: lines 5-7 recite “rs4503083; and.” This recitation is interpreted as intending to mean “rs4503083.”
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) – Indefiniteness
Newly Applied
Claims 1-5, 7-8, 10, 13, and 15-23 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1, 2, and 21 recite SNP alleles in an unconventional manner that makes unclear the intended limitation of the respective claim in the recitations “a TT allele at rs10109853” in line 9 of claim 1, “CC at single nucleotide polymorphism (SNP) site rs4503083” in line 5 of claim 2, and “a TT allele at rs10109853” in lines 7-8 of claim 21. An SNP is a single nucleotide polymorphism, and so an allele for a specific SNP site should be a single nucleotide, like the recited “a C allele at rs4503083” in line 8 of claim 1. In contrast, a diploid genotype at an SNP site may be represented N1/N2 (where each N# is the nucleotide at the SNP site for each of two copies of the allele carried in a diploid genotype). Due to the recitation of two nucleotides, using the recitation of “a TT allele at rs10109853” in claim 1 as an example, it is unclear whether Applicant intends to claim a T allele at rs10109853, a T/T genotype at rs10109853, or an unconventional interpretation of a SNP allele as an insertion mutation at rs10109853 causing the single nucleotide to be mutated into two consecutive thymine nucleotides TT. For the purpose of examination, these recitations of “TT”, “CC”, and “TT” are interpreted as “T”, “C”, and “T” to be consistent with the standard understanding of an SNP allele. Claims 2-5, 7-8, 10, 13, 15-20, and 22-23 are rejected based on their dependency on claim 1.
Claim 1, as interpreted in the rejection of claims 1, 2, and 21 above, recites “a mutation of least one of the Indoleamine 2,3-dioxygenase 2 (IDO2) gene alleles at the single nucleotide polymorphism (SNP) site selected from a C allele at rs4503083 or a [T] allele at rs10109853”. It is unclear whether the claim is intended to be limited to (1) the detection of the mutation of the nucleotide at the rs4503083 SNP site to a C allele or the nucleotide at the rs10109853 site to a T allele, or (2) the detection of a mutation from a C allele into a different nucleotide at the rs4503083 SNP site or from a T allele into a different nucleotide at the rs10109853 SNP site. Additionally, the rs4503083 SNP is a substitution from a wild-type T allele to a mutant A allele (see rs4503083 RefSNP Report, IDS Cite No. 73 in IDS filed 15 June 2023) and the rs10109853 SNP is a substitution from a wild-type C allele to a mutant T allele (see rs10109853 RefSNP Report, IDS Cite No. 74 in IDS filed 15 June 2023), so the alleles listed in the claim are not the wild-type alleles. This fact raises a third potential interpretation that rs4503083 and rs10109853 were swapped, wherein the claim should read “selected from a C allele at rs10109853 or a T allele at rs4503083”, which would be stating the wild-type allele at the respective SNP site, making clear that the claim limitation is for the detection of a mutation from at least one of the given wild-type alleles into a different nucleotide. For the purpose of examination, the third interpretation that rs4503083 and rs10109853 were swapped is used and the claim is interpreted as requiring the detection of a mutation of at least one of the wild-type alleles at SNP sites rs4503083 or rs10109853 into a mutant allele. Claims 2-5, 7-8, 10, 13, 15-20, and 22-23 are rejected based on their dependency on claim 1.
Claim 2 as interpreted in the rejection of claims 1, 2, and 21 above, recites “a mutation at the following wildtype alleles: [C] at single nucleotide polymorphism (SNP) site rs4503083”. This recitation is unclear for the same reasons as given for the rejection of similar language in claim 1 above. For the purpose of examination, this is interpreted as referring to the correct wildtype allele for SNP site rs4503083, which is a T, rather than a C.
Claim 21 as interpreted in the rejection of claims 1, 2, and 21 above, recites “a mutation of the Indoleamine 2,3-dioxygenase 2 (IDO2) gene at the single nucleotide polymorphism (SNP) site selected from a C allele at rs4503083 and a [T] allele at rs10109853”. This recitation is unclear for the same reasons as given for the rejection of similar language in claim 1 above. For the purpose of examination, the same interpretation is also used.
Claims 1 and 21 recite the limitation "said subject" in lines 4 and 3, respectively and the limitation “the subject” in lines 5-6 and 4-5, respectively. There is insufficient antecedent basis for these limitations in the claims, since these recitations may refer to the subject of claim 1 line 1 and claim 21 line 1 or the biological subject of claim 1 line 4 and claim 21 line 3. Claims 2-5, 7-8, 10, 13, 15-20, and 22-23 are rejected based on their dependency on claim 1.
Claim 13 recites “wherein the cancer is pancreatic cancer or pancreatic ductal adenocarcinoma, melanoma, […], lung cancer, and neuroendocrine cancer, or glioblastoma” (emphasis added). The use of mixed ‘and’ and ‘or’ phrases makes it unclear whether the list of cancers provided in claim 13 is a list of alternatives wherein the cancer is any one of pancreatic cancer through glioblastoma, or whether the cancer is either pancreatic cancer, glioblastoma, or a combination of the cancers listed from PDAC through neuroendocrine cancer. For the purpose of examination, claim 13 is interpreted as a list of alternatives wherein the cancer can be any one of the listed cancers.
Claim 18 recites the limitation "the disease" in line 1. There is insufficient antecedent basis for this limitation in the claim.
The term “more” in claim 19 is a relative term which renders the claim indefinite. The term “more” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Therefore, one of ordinary skill in the art would not be reasonably apprised of the degree of responsiveness to radiotherapy required by claim 19.
Claim Rejections - 35 USC § 112(b) – Indefiniteness
Maintained, Modified
Claim 19 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 19 is unclear over the recitation: “…subject is more responsive to radiotherapy…”, as the claim does not state any other therapy that the responsiveness is compared against (e.g. is the subject more responsive to radiotherapy than the subject is to chemotherapy? Is the subject more responsive to radiotherapy than a control subject is to radiotherapy?). For the purpose of examination, this limitation is interpreted as including any response to radiotherapy.
Response to Arguments
Applicant’s argument, see pages 9 of Applicant's response, filed 4 August 2025, with respect to the rejection of claim 19 under 35 U.S.C. Section 112(b) has been fully considered and is not persuasive. Applicant argues that the amendment to claim 19 provides antecedent basis for the rejected phrase “…subject is more responsive to radiotherapy”. However, the rejection of claim 19 under 35 U.S.C. 112(b) in the action dated 2 April 2025 is not a rejection based on lack of antecedent basis for the therapies, but rather because the word “more” implies a comparison between the treatment of the subject with radiotherapy in comparison to some other treatment that is left unclear. It is noted that in this new non-final office action claim 19 is further rejected under 35 U.S.C. 112(b) in the Newly Applied section because “more” is a relative term, which is a separate rejection.
Claim Rejections - 35 USC § 112(a) – New Matter
Claims 1-5, 7-8, 10, 13, and 15-23 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.
Regarding claims 1-5, 7-8, 10, 13, and 15-23, a first rejection of the claims for adequate written description in the applicant is relevant to the amendment to the claims replacing each recitation in the claims of “rs4503084” with “rs4503083”, which introduces new matter in claims 1, 2, and 21 directly and claims 2-5, 7-8, 10, 13, 15-20, and 22-23 by virtue to their dependency on claim 1. Though Applicant submits that this amendment stems from a typographical error (Applicant’s response, page 6, last 2 lines) and has support in the original specification including Table 1 (Applicant’s response, page 7, last paragraph), this amendment is not supported in the original description because the original description describes both rs4503084 (ex: Spec filed 10 March 2022, page 2 lines 15 and 22; page 10 line 12) and rs4503083 (ex: Table 1), so it is unclear whether the presence of both in the disclosure is due to them being two different SNPs or due to a typographical error. As such, the supposed typographical error and its appropriate correction would not be immediately clear to one of ordinary skill in the art (MPEP §2163.07 II.), so one of ordinary skill in the art would not be able to ascertain that, at the time the application was filed, the inventor was in possession of the claimed invention including “rs4503083”.
Regarding claims 1-5, 7-8, 10, 13, and 15-23, a second rejection of the claims for adequate written description in the applicant is relevant to the amendment of claims 1 and 21 to recite “a C allele at rs4503083”, which introduces new matter in claims 1 and 21 directly and claims 2-5, 7-8, 10, 13, 15-20, and 22-23 by virtue of their dependency on claim 1. Though Applicant submits that this amendment is supported by the specification as filed (Applicant’s response, page 10 lines 2-4), this amendment is not supported by the original description because the original description describes “following wildtype alleles: i. CC at single nucleotide polymorphism (SNP) site rs4503084” (Spec filed 10 March 2022, page 11 lines 15-16; Claims filed 10 March 2022 claim 2). Even should the amendments to the Spec and Claims changing rs4503084 to rs4503083 be accepted pursuant to future arguments (see rejection for amendment of rs4503084 to rs4503083 being new matter in above paragraph), this only discloses a CC allele, not a C allele. Additionally, Table 1 does not support a C allele at rs4503083 because Table 1 in the 3rd column from the left describes the SNP allele rs4503083 encoding an amino acid substitution R325W wherein the allele for the wildtype at the SNP is C, which is contrary to established scientific fact in the art that the SNP allele rs4503083 is a T>A substitution resulting in a Y359Stop wherein the allele for the wildtype at the SNP is T (see rs4503083 RefSNP Report, IDS Cite No. 73 in IDS filed 15 June 2023). Table 1’s recitation of R325W introduces further contradiction, since the known SNPs in IDO2 are rs4503083 causing Y359Stop (also called Y359X) and rs10109853 causing R248W (see Table 2 of instant Spec; see IDS Cite No. 73 and 74 from IDS filed 15 June 2023), neither of which cause R325W. These contradictions make it unclear whether Table 1 teaches a new interpretation of rs4503083 as having a wildtype C allele and being at a different position than the SNP site rs4503083 known in the art or whether Table 1 contains multiple errors. As such, one of ordinary skill in the art would not be able to ascertain that, at the time the application was filed, the inventor was in possession of the claimed invention including “a C allele at rs4503083”.
Claim Rejections - 35 USC § 112(a) - Written Description
Maintained, Modified – Additional Claims Newly Applied
Claims 1-5, 7-8, 10, 13, and 15-23 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.
Regarding claims 1-5, 7-8, 10, 13, and 15-23, the rejection of the claims for lack of adequate written description in the application is relevant to the presence of a mutation at the SNP sites rs4503083 or rs10109853 and the associated prediction of treatment response or assessment of cancer onset risk.
The disclosure teaches only particular alleles leading to particular changes to the IDO2 protein (Table 1, a T>A mutation at SNP site rs10109853 and a C>T mutation at SNP site rs4503083), whereas the claims encompass any mutation of the recited SNP sites which could result in different changes to the protein. The disclosure teaches that the genotype of a human subject with PDAC may be associated with treatment-specific survival (Spec, page 24, lines 25-29), that the genotype of a human subject with brain metastases may be associated with treatment-specific survival (Spec, page 13, lines 20-26), that the genotype of a human subject with melanoma may be associated with treatment-specific survival (Spec Example 5, page 44 line 19 - page 45 line 4), or that the genotype of a mouse with PDAC may be associated with disease progression (Spec Example 1, page 22, lines 7-10). However, the disclosure does not teach any/all content at the SNPs as generically encompassed by the claims (e.g., presence of any substitution mutation). Further the disclosure does not teach a method for predicting responsiveness to treatment nor a method for predicting cancer onset, as required by the claims. Although the disclosure teaches cases of data analysis that show the above listed associations in humans with PDAC, brain metastases, or melanoma and a specific genotype having different survivability when treated compared to subjects with a different genotype with the same disease and treatment, they have not described any method for prediction of response to treatment or prediction of onset of cancer. It is possible these data could be used to develop these methods, but possession may not be shown merely by describing how possession may be obtained. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. This finding is also emphasized in Ex Parte Kubin (No. 2007-0819, Bd. Pat. App. & Int. May 31, 2007), wherein it is stated that:
"Although there is often significant overlap" between the enablement and written description requirements, "they are nonetheless independent of each other." University of Rochester, 358 F.3d at 921, 69 USPQ2d at 1891. An "invention may be enabled even though it has not been described." Such is the situation here. While we conclude one skilled in the art would have been able to make and use the full scope of claim 73 through routine experimentation, we find Appellants did not describe the invention of claim 73 sufficiently to show they had possession of the claimed genus of nucleic acids. See, e.g., Noelle V. Lederman, Application/Control Number: 17/517,431 355 F.3d 1343, 1348, 69 USPQ2d 1508, 1513 (Fed. Cir. 2004) ("invention is, for purposes of the "written description' inquiry, whatever is now claimed").
Therefore, the suggestion of an assumed similar association between the treatment-specific survival of the subject with a particular genotype who is diagnosed with PDAC, brain metastases, or melanoma and the treatment-specific survival of a subject with the same genotype but a different cancer, chronic infection, autoimmune disease, or retinopathy is not sufficient to establish that Applicant was in possession of the invention as broadly claimed. In addition, the association with a genotype and treatment-specific survivability of PDAC, brain metastases, or melanoma is not the same as a method of predicting responsiveness to treatment nor a method for predicting cancer onset, and is not sufficient to establish that Applicant was in possession of the invention as broadly claimed. Finally, an association between genotype and survivability or onset of a limited set of specific diseases (PDAC, brain metastases, and melanoma) cannot be blanket applied to any cancer, chronic infection, retinopathy or autoimmune disorder because each of these are broad genera of diseases containing species that vary in their genetic correlations and effectiveness of therapeutics, making predicting responsiveness to treatment and disease onset highly unpredictable across the genera. See MPEP §2163 II. A. 3. (a) ii): “Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (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.")”. Therefore, suggesting that diseases of these genera may be related is not sufficient to establish that applicant was in possession of the invention as broadly claimed.
Based on this analysis, one of ordinary skill in the art would conclude that applicant was not in possession of the claimed prediction of the responsiveness to treatment or predicting onset of any cancer, chronic infection, autoimmune disease, or retinopathy based on genotyping of the claimed SNP sites, as they are not described in the disclosure.
Response to Arguments
Applicant's arguments, see pages 9-10 of Applicant's response, filed 4 August 2025, with respect to rejections under 35 U.S.C. Section 112(a) for failing to comply with the written description requirement have been fully considered but they are not persuasive.
Applicant’s argument on page 10 lines 5-10 of Applicant’s response that page 1 lines 25-29 of the specification as filed teaches that inhibition IDO with treatment of indoximod improves the treatment of retinopathies, chronic diseases, and autoimmune diseases and that page 1 lines 30-33 and page 2 lines 1-5 teach a connection between loss of IDO2 and autoimmune diseases is not persuasive because these are each broad genera of diseases and the recited portion of the specification merely names these genera as being studied with IDO inhibitors and gives a single species of treating rheumatoid arthritis. MPEP §2163 II. A. 3. (a) ii):
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 (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., 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 inventor was in possession of the claimed genus
The recited studies fail to teach specific characteristics or sufficient representative species to show the inventor was in possession of the claimed genus. Teaching a connection between IDO2 activity and rheumatoid arthritis is not sufficient to show that the inventor had possession of the claimed all autoimmune diseases, particularly when the study by Agliardi et al. that is cited in this portion of the specification identifies that a different autoimmune disease was not, in fact, connected with IDO2 activity.
Applicant’s argument on page 10 lines 11-19 of Applicant’s response that the disclosure of a connection between the recited SNPs with brain cancer, melanoma, and PDAC is not persuasive. While applicant does disclose 3 species of cancer for which the written description requirement is met, all cancers is a broad genus, so the standard for whether the written description requirement is met for the genus is whether a representative number of species are described. See MPEP §2163 II. A. 3. (a) ii): “Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (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.")”. As cancer is a broad and unpredictable genus, a showing that 3 specific cancers are connected to IDO2 activity does not lead one of ordinary skill in the art to presume that all cancers are connected to IDO2 activity and therefore would not understand the inventor to be in possession of the claimed genus of all cancers.
Applicant’s argument on page 9 lines 32-33, page 10 lines 1-4, and page 10 lines 20-22 of Applicant’s response that the amendments to claims 1 and 21 to recite 1) that the disease is a cancer, chronic infection, autoimmune disease, or retinopathy, and 2) that the SNP sites include specific alleles recited in Table 1 is not persuasive. The limitation of the disease to being a cancer, chronic disease, infection, autoimmune disease, or retinopathy is not sufficient to comply with the written description requirement as discussed in the two paragraphs above. While the limitation of the mutations at the SNP sites to being mutations to specific alleles that are supported in the specification would be sufficient to comply with the written description requirement, contrary to Applicant’s arguments the amendments have failed to do so. See the rejections of claims 1, 2, and 21 together as well as separately under 35 U.S.C. 112(b) (the first 4 rejections of the section) for a full explanation of why these amendments have made the claim language unclear, resulting in examiner’s interpretation of claim 1 as claiming detecting either a mutation from a wild-type T allele at SNP site rs4503083 or a mutation from a wild-type C allele at SNP site rs10109853 (and similar interpretations of claims 2 and 21). These claim interpretations result in claims 1, 2, and 21 having scopes that include the mutation of the SNP site at rs4503083 from a T into an A, C, or G and the mutation of the SNP site at 10109853 from a C into an A, T, or G, despite the specification only providing support for the mutation of the SNP site at rs4503083 from a T into an A and the mutation of the SNP site at 10109853 from a C into a T.
Claim Rejections - 35 USC § 112 – Scope of Enablement
Maintained, Modified
Claims 1-5, 7-8, 10, 13, and 15-23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for certain alleles being associated with survivability when the subject has PDAC, brain metastases, or melanoma when given specific treatments, does not reasonably provide enablement for the generic breadth of the claims with regard to any response to any treatment of any cancer, chronic infection, autoimmune disease, or retinopathy, the response to treatment of any subject organism, or the assessment of risk of cancer onset in any subject organism for any cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Nature of the invention and breadth of the claims
The claims are drawn to a method comprising predicting the responsiveness of a subject having a disease to a treatment regimen, the subject having a genotype in regards to the IDO2 gene, and associated the presence of a mutation of at least one allele at SNP sites rs4503083 and rs10109853. Claims 1-5, 7-8, 10, 15-17, and 19 are sufficiently broad to encompass any cancer, chronic infection, autoimmune disease or retinopathy, any treatment regimen; claims 1-5, 7-8, 10, and 15-21 are sufficiently broad to encompass any cancer; claims 1-5, 7-8, 10, 13, and 15-23 are sufficiently broad to encompass any mammalian animal subject (subject limited in Spec, page 6, lines 8-9); and claims 1-2, 13, 16, and 22-23 are sufficiently broad to encompass any treatment.
Direction provided by the specification and working example
The instant specification provides examples where the genotype of a human subject with PDAC may be associated with radiotherapy treatment-specific survival (Spec, page 24, lines 25-29), that the genotype of a human subject with brain metastases may be associated with radiotherapy treatment-specific survival (Spec, page 13, lines 20-26), that the genotype of a human subject with melanoma may be associated with radiotherapy combined with indoximod treatment-specific survival (Spec Example 5, page 44 line 19 - page 45 line 4), or that the genotype of a mouse with PDAC may be associated with disease progression (Spec Example 1, page 22, lines 7-10). Though the specification teaches these associations, the specification does not teach a method for predicting responsiveness of a subject to a treatment regimen, nor a method for assessing the risk of a subject for the onset of cancer.
State of the art, level of skill in the art and level of unpredictability
While the state of the art and level of skill in the art with regard analysis of human genotypes is high, the unpredictability of associating all variation in the IDO2 SNPs to response to treatment of disease or to the onset or progression of disease is higher. Such unpredictability is demonstrated by the related art.
The art of Merlo et al. (2014)(IDS Cite No. 40 in IDS filed 15 June 2023) teaches that the genotype of IDO2 influences the response of the KRN mouse model of the autoimmune disease rheumatoid arthritis to treatment with the IDO pathway inhibitor 1MT. However, the art of Agliardi et al. (2017)(IDS Cite No. 15 in IDS filed 15 June 2023) teaches that, in the analyzed human population, the rs10109853 and rs4503083 IDO2 SNPs do not show any association with the risk or age of onset for the autoimmune disease multiple sclerosis. This demonstrates the unpredictability in the art and variability within the broad genus of autoimmune diseases, wherein the IDO2 genotype may be predictive for the treatment response of one type of subject to one autoimmune disease but also is not associated with a separate autoimmune disease.
Where the claims are specifically drawn to predicting cancer onset or subject responsiveness to disease treatment associated with any mutation at the target SNP sites, it is relevant to point out the unpredictability of cancer onset and responsiveness to disease treatment associated with genotype. Metz et al. (2007) defined two SNPs associated with loss of enzymatic activity in IDO2 that may be related to disease progression (e.g., Metz et al., page 7086, para 2), but also states that there were likely other transcription start sites on the human IDO2 (e.g., Metz et al., page 7084, last para; 7086, first para), suggesting the possibility that not all SNPs would have the same effect on disease progression or response to treatment, or that mutations at one SNP site may not have the suggested impact when absent a specific condition at other SNP sites on the same gene. Metz et al. further states that there is likely cooperation between IDO and IDO2 in immune regulation (e.g., Metz et al., page 7087, right column, para 1), suggesting that mutations or absence of mutations in the claimed target SNP sites may not have the same effect depending on the presence or absence of mutations in the IDO gene.
Quantity of experimentation required
A large, unpredictable, and prohibitive amount of experimentation would be required to make and use the claimed invention. Such experimentation would require case:control analysis to establish the predictive indication of all possible mutations at the claimed SNP sites on the IDO2 gene on all possible treatments of all possible cancers, chronic infections, autoimmune diseases, and retinopathies in all mammalian subjects.
Conclusion
Taking into consideration the factors outlined above, including the nature of the invention, breadth of the claims, the state of the art, the level of skill in the art and its high level of unpredictability, the lack of guidance by the applicant and the particular examples, it is the conclusion that an undue amount of experimentation would be required to make and use the claimed invention in the full scope as claimed.
Response to Arguments
Applicant's arguments, see pages 10-11 of Applicant's response, filed 4 August 2025, with respect to rejections under 35 U.S.C. Section 112(a) for failing to comply with the enablement requirement have been fully considered but they are not persuasive.
Applicant’s argument on pages 10-11 of Applicant’s response that the amended claims, reciting specific SNP alleles and diseases (cancer, chronic infection, autoimmune infection, or retinopathy) are enabled because various studies have shown improved outcomes when treating such diseases in combination with reduced IDO2 activity is unpersuasive. While those studies provide support for why one of skill in the art would be able to apply the claimed methods relating to IDO2 and disease treatment or risk assessment to the diseases taught in those studies, they do not provide support for enablement of all diseases of the broad genera that they belong to. For example, while the paragraphs in the specification that the Applicant points to cite a study by Merlo et al. that found connected the status of the IDO2 gene with treatment effectiveness for one autoimmune disease, rheumatoid arthritis, the same section points out another study, by Agliardi et al., that found no connection between a different autoimmune disease, multiple sclerosis, and IDO2 activity. This example demonstrates the unpredictability of the art in these broad genera. This unpredictability means that for one of ordinary skill in the art to be enabled to practice the claimed invention on these broad genera as claimed they would be required test the method on every possible disease claimed to ascertain how the method can be applied to each and every one of those diseases. Applicant further points to the Examiner’s rationale that a person of ordinary skill in the art would recognize that the similar method of Eldredge could be applied to diseases with similar associations with the IDO/TDO pathway. However, this rationale only applies to disease with similar associations with the IDO/TDO pathway. Neither the disclosure of the applicant nor the prior art teach that every disease in the claimed broad genera of cancer, chronic infection, autoimmune disease, or retinopathy has sufficient association with the activity of the IDO/TDO pathway to enable a person of ordinary skill in the art to practice the invention on all diseases in these genera.
Claim Rejections - 35 USC § 101
Maintained, Modified – Additional Claims Newly Applied
Claims 1-5, 7-8, 10, 13, and 15-23 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., an abstract idea) without significantly more. The claims recite "predicting the responsiveness" or "assessing the risk". This judicial exception is not integrated into a practical application and the rationale is described below:
The unpatentability of abstract ideas was confirmed by the U.S. Supreme Court in Bilski V. Kappos, No. 08-964, 2010 WL 2555192 (June 28, 2010) and in Alice Corp. V. CLS Bank Inti, 134 S. Ct. 2347, 2354 (2014).
The following inquiries are used to determine whether a claim is drawn to patent-eligible subject matter:
Step 1. Is the claim to a process, machine, manufacture, or composition of matter? Yes, the claims are directed to processes.
Step 2A, prong 1. Is the claim directed to a law of nature, a natural phenomenon, or an abstract idea (judicially recognized exceptions)? Yes, where the claims recite predicting responsiveness or assessing a risk, such concepts are abstract ideas as they can be performed in one’s head by a skilled person looking at data.
Step 2A, prong 2. Does the claim recite additional elements that integrate the exception into a practical application? No, the judicial exceptions to which the claims are directed are not integrated into a practical application because the rejected claims do not require any particular practical steps that are not considered insignificant extra-solution activity due to being mere data gathering through routine and conventional methods, such as obtaining DNA and performing a genotype assay.
Step 2B. Does the claim recite additional elements that amount to significantly more than the judicial exception? No, the claims include practical steps of obtaining DNA and performing a genotyping assay, but the broadly recited steps are properly considered routine and conventional and are mere data gathering, so the claims are not significantly more than the judicial exceptions to which they are directed. Where the claims recite limitations of genotyping subjects (e.g., claim 1 and claim 21), these steps are regularly found in the art and include SNPs that are known in the art (e.g., Eldredge et al, page 317, left column, para 2). Where the claims recite limitations relating to the treatment of subjects (such as claim 3), it is noted that none of the claims do not actually require the treatment to be effected (as required in MPEP §2106.04(d)(2) for a particular treatment to integrate a judicial exception), but only limit the treatment regimen that the abstract idea of predicting responsiveness to a treatment acts upon. Merely modifying the conditions of the abstract idea (such as an abstract idea x+y=z being modified by the limitation of x>2) does not make it any more than an abstract idea.
For these reasons, claims 1-5, 7-8, 10, 13, and 15-23 are rejected under USC 35 section 101 as being directed to non-statutory subject matter.
Response to Arguments
Applicant's arguments, see pages 11-12 of Applicant's response, filed 4 August 2025, with respect to rejections under 35 U.S.C. Section 101 have been fully considered and are not persuasive. Applicant argues that, as claim 2 was excluded from the previous rejection, the incorporation of the features of claim 2 into claims 1 and 21 is sufficient for claims 1 and 21 to be patent eligible subject matter. However, the incorporated features of obtaining DNA from a biological subject of said subject and contacting the DNA sample from the subject with reagents are broadly recited steps of mere data gathering that are routine and conventional, so the claims fail to amount to significantly more. The rejection has been modified to increase clarity of the above reasoning and to further reject claims 2-5, 7-8, 10, 13, 15-20, and 22-23.
Claim Rejections - 35 USC § 102
Maintained, Modified
Claims 1-5, 7-8, 13, and 15-19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Eldredge et al. (IDS Cite No. 25 in IDS filed 15 June 2023)(“Concurrent whole brain radiotherapy and short-course chloroquine in patients with brain metastases: a pilot trial” J Radiat Oncol 2, pages 315-321 (2013)), herein Eldredge.
Regarding claim 1, Eldredge teaches a method of treating cancer and an association between the response to treatment and specific genotypes of cancer patients (Eldredge, title, abstract). Eldredge teaches obtaining DNA from a biological subject and performing a genotype assay comprising contacting the DNA sample with reagents and that the genotypes determined are the IDO2 SNPs, rs10109853, where the C>T mutation at this site is associated with attenuation of catalytic activity of the IDO2 enzyme, and rs4503083, where the T>A mutation at this site is associated with a truncated IDO2 enzyme completely lacking its catalytic activity (Eldredge, page 317, left column, para 3). Eldredge teaches that the presence of a mutation in at least one of the SNPs indicates that the subject is likely to respond positively to a radiotherapy treatment, since they observed high rates of radiologic response in patients with enzymatically ablative SNPs (Eldredge, page 318, right column, para 4).
Regarding claim 2, Eldredge teaches the method according to claim 1, further comprising: (a) obtaining DNA from a biological sample of said subject (Eldredge, page 317, right column, para 3); (b) contacting the DNA sample from the subject with reagents to determine the presence of a mutation at the wildtype allele T at SNP site 4503083 (Eldredge, page 317, left column, para 3).
Regarding claim 3, Eldredge teaches the method according to claim 1, wherein the treatment regimen involves treatment with an inhibitor of Indoleamine 2,3-dioxygenase 2 (IDO), an inhibitor of tryptophan 2,3- dioxygenase (TDO), or an inhibitor of the IDO/TDO pathway (Eldredge, page 317, left column, para 2).
Regarding claim 4, Eldredge teaches the method according to claim 3, wherein subjects with at least one wildtype allele are more likely to respond positively to treatment with an IDO or TDO inhibitor than subjects lacking active alleles (e.g., Eldredge, abstract).
Regarding claim 5, Eldredge teaches the method according to claim 3, wherein subjects with homozygous mutations at the SNPs were less likely to respond to a treatment with IDO inhibitor (chloroquine) than subjects with wild-type alleles (Eldredge, page 318, right column, para 4).
Regarding claim 7, Eldredge teaches the method according to claim 1, wherein said treatment regimen involves a combination of treatment with an inhibitor of Indoleamine 2,3-dioxygenase 2 (IDO), an inhibitor of tryptophan 2,3-dioxygenase (TDO), or an inhibitor of the IDO/TDO pathway with a second therapy (Eldredge, page 317, left column, para 2; page 316, right column, last para).
Regarding claim 8, Eldredge teaches the method according to claim 7, wherein the second therapy is a radiotherapy, chemotherapy or immunotherapy (Eldredge, page 316, right column, last para).
Regarding claim 13, Eldredge teaches a method wherein the cancer is breast cancer, brain cancer, lung cancer, or ovarian cancer (Eldredge, table 1).
Regarding claim 15, Eldredge teaches the method according to claim 8, wherein the occurrence of a biallelic inactivating mutation at either or both SNP sites indicates that the subject would have a positive response to said treatment involving radiotherapy (Eldredge, page 318, right column, para 4; page 316, right column, last para).
Regarding claim 16, Eldredge teaches the method according to claim 1, wherein the subject's genotype showing inactivating SNP site mutations on a single allele indicates that the subject would have a positive response to said treatment (Eldredge, page 318, right column, para 3).
Regarding claim 17, Eldredge teaches the method according to claim 8, wherein the subject's genotype showing wild-type nucleotides at both SNP sites indicates that the subject would have a positive response to said treatment involving chemotherapy when compared to an untreated control subject (Eldredge, page 316, left column, para 4).
Regarding claim 18, Eldredge teaches the method according to claim 8, wherein the disease is cancer and the second therapy is radiation therapy and the inhibitor is chloroquine (Eldredge, page 317, left column, para 2; page 316, right column, last para).
Regarding claim 19, Eldredge teaches the method according to claim 8, wherein subject demonstrating biallelic mutation at two SNP sites indicates that said subject is responsive to radiotherapy (Eldredge, page 318, right column, para 4; page 316, right column, last para).
Therefore, claims 1-5, 7-8, 13 and 15-19 are anticipated by Eldredge.
Response to Arguments
Applicant's arguments, see page 12 of Applicant's response, filed 4 August 2025, with respect to rejections under 35 U.S.C. Section 102 have been fully considered but they are not persuasive. In response to applicant's argument that Eldredge does not teach the amended claim wherein the SNP at rs10109853 has a TT genotype and the SNP at rs4503083 has a C allele, Examiner first directs Applicant to the rejections of claims 1, 2, and 21 together and independently under 35 U.S.C. 112(b) as necessitated by this amendment, which has led Examiner to the interpretation of the recitations of detecting the presence of a mutation at a SNP site as requiring the detection of a mutation at SNP site rs4503083 or rs10109853 from their known wild-type alleles in the art (respectively T and C). Under this interpretation, Eldredge teaches the claimed limitation, as Eldredge recites the genotyping of mutations from the wild-type alleles at both rs10109853 and rs4503083 in the paragraph on IDO2 genotyping on page 317, left column.
Claim Rejections - 35 USC § 102
Newly Added
Claim 21 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Nevler et al. (IDS Cite No. 51 in IDS filed 15 June 2023)(“A Sub-Type of Familial Pancreatic Cancer: Evidence and Implications of Loss-of-Function Polymorphisms in Indoleamine-2,3-Dioxygenase-2” J Am Coll Surg 226(4), pages 596-603 (2018)), herein Nevler.
Regarding claim 21, Nevler teaches a method of assessing the risk of a subject for the onset of cancer comprising obtaining DNA from a subject and performing a genotype assay to determine the presence of a mutation of the Indoleamine 2,3-dioxygenase 2 (ID02) gene at the single nucleotide polymorphism (SNP) sites rs4503083 (causing the Y359Stop mutation) and rs10109853 (causing the R248W mutation), wherein the presence of the mutation at rs4503083 that inactivates the ID02 activity of both alleles indicates that said subject has a decreased risk of cancer onset (Nevler, title, page 596, results para, study design para, conclusions para; page 598, right column, para 2).
Therefore, claim 21 is anticipated by Nevler.
Claim Rejections - 35 USC § 103
Maintained, Modified
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 10 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Eldredge et al. (IDS Cite No. 25 in IDS filed 15 June 2023)(“Concurrent whole brain radiotherapy and short-course chloroquine in patients with brain metastases: a pilot trial” J Radiat Oncol 2, pages 315-321 (2013)), herein Eldredge, as applied to claims 1-5, 7-8, 13 and 15-19 above, in view of Nevler et al. (IDS Cite No. 51 in IDS filed 15 June 2023)(“A Sub-Type of Familial Pancreatic Cancer: Evidence and Implications of Loss-of-Function Polymorphisms in Indoleamine-2,3-Dioxygenase-2” J Am Coll Surg 226(4), pages 596-603 (2018)), herein Nevler.
Regarding claim 10, Eldredge teaches the method of claim 8 and an association with IDO2 genotype and cancer treatment as described above. However, Eldredge does not teach the use of an anti-PD1 composition or dendritic cell therapy. This deficiency is made up for in the teachings of Nevler.
Regarding claim 10, Nevler teaches a method wherein an immunotherapy comprising the administration of an anti-PD1 composition is used to treat cancer patients with inactive IDO2 genotypes (Nevler, page 602, right column, last para; page 603, right column, para 2).
Regarding claim 22, Nevler teaches a method wherein the subject with SNPs related to IDO2 inactivation have pancreatic cancer (Nevler; title, page 596, results para, study design para, conclusions para, note R248W is the mutation of the allele at SNP site rs10109853 and Y359Stop is the mutation of the allele at SNP site rs4503083).
It would have been prima facie obvious before the effective filing date of the claimed invention for one having ordinary skill in the art to have recognized that the method of Eldredge could be applied to other diseases with similar associations with IDO/TDO pathway, and to apply treatments relevant to that pathway. Thus, the combination of the method of Nevler to the method of Eldredge et al would have been a simple combination of known methods to yield predictable results.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Eldredge et al. (IDS Cite No. 25 in IDS filed 15 June 2023)(“Concurrent whole brain radiotherapy and short-course chloroquine in patients with brain metastases: a pilot trial” J Radiat Oncol 2, pages 315-321 (2013)), herein Eldredge, as applied to claims 1-5, 7-8, 13 and 15-19 above, in view Bahary et al. (“Phase 2 trial of the indoleamine 2,3-dioxygenase pathway (IDO) inhibitor indoximod plus gemcitabine/nab-paclitaxel for the treatment of metastatic pancreas cancer: Interim analysis” J Clin Oncol 34(Suppl 15), page S3020 (2016)), herein Bahary.
Regarding claim 20, Eldredge teaches the method of claim 8 and an association with IDO2 genotype and cancer treatment as described above. However, Eldredge does not teach a method where the treatment of cancer is gemcitabine and indoximod. However, this deficiency is made up for in the teachings of Bahary.
Regarding claim 20, Bahary teaches a method wherein the disease is cancer, the chemotherapeutic is gemcitabine and the IDO inhibitor is indoximod (Bahary, title; conclusion).
It would have been prima facie obvious before the effective filing date of the claimed invention for one having ordinary skill in the art to have recognized that the treatment of Bahary, with IDO inhibitor, would affect other diseases to which IDO inhibitors would apply, and if the treatment regimen was effective in this case, it could be applied to other similar disease. Where the prior art teaches the treatment regimen as applied to disease that affected by the same enzymatic pathway in the same way, a person of ordinary skill has good reason to pursue the known options within their technical grasp to apply treatment of disease. If this leads to anticipated success, it is the product not of innovation, but of ordinary skill and common sense.
Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over Eldredge et al. (IDS Cite No. 25 in IDS filed 15 June 2023)(“Concurrent whole brain radiotherapy and short-course chloroquine in patients with brain metastases: a pilot trial” J Radiat Oncol 2, pages 315-321 (2013)), herein Eldredge, as applied to claims 1-5, 7-8, 13 and 15-19 above, in view of Bilir and Sarisozen (“Indoleamine 2,3-dioxygenase (IDO): Only an enzyme or a checkpoint controller?” Journal of Oncological Sciences, 3(2), pages 52-56 (2017).
Regarding claim 23, Eldredge teaches the method of claim 1 and the association of IDO2 genotype and cancer treatment as described above. However, Eldredge does not teach a specific association with melanoma. This deficiency is made up for in the teachings of Bilir and Sarisozen.
Regarding claim 23, Bilir and Sarisozen teach a method of treating a subject with cancer with an IDO inhibitor wherein the subject's IDO associated cancer is melanoma (Bilir and Sarisozen, page 54, right column, para 2).
It would have been prima facie obvious before the effective filing date of the claimed invention for one having ordinary skill in the art to have recognized that the method of Eldredge could be applied to other cancers with similar associations with IDO/TDO pathway, such as Bilir and Sarisozen’s teaching of melanoma responding to treatment targeting the IDO/TDO pathway. Thus, the combination of the method of Bilir and Sarisozen to the method of Eldredge would have been a simple combination of known methods to yield predictable results.
Response to Arguments
Applicant's arguments, see pages 12-13 of Applicant's response, filed 4 August 2025, with respect to rejections of claims 10 and 22, 20, and 23 under 35 U.S.C. Section 103 have been fully considered but they are not persuasive. In response to applicant's arguments that the combinations of Eldredge and Nevler, Eldredge and Bahary, and Eldredge and Bilir and Sarioszen fail to teach the recited SNP alleles, it is noted that Eldredge does teach detecting mutations of the recited SNP alleles as discussed in the above response to Applicant’s arguments with respect to rejections under 35 U.S.C. Section 102.
Conclusion
Claims 1-5, 7-8, 10, 13, and 15-23 are rejected. This action is Non-Final.
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/JEFFREY BELLAH/Examiner, Art Unit 1683
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683
