, DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status and Formal matters
This action is in response to papers filed 11/19/2025.
Claims 1, 3, 5-6, 8, 10-11, 19, 136-140 are pending.
Claim 1 has been amended.
Claims 137-140 have been added by amendment.
Applicant's election with traverse of group I, HLA-A in the reply filed on 7/18/2025 is acknowledged. The traversal is on the ground(s) that the groups have a shared technical feature of detecting allele frequency. This is not found persuasive because McGranahan (cell (2017) 171, 1259-1271) teaches detection of allele frequency. Thus the claims lack a special technical feature over the prior art.
The response traverses the species election for the reasons asserted previously, which are not persuasive for the reasons of record.
Claims 36-40, 44-45, 47- withdrawn from further consideration pursuant to 37 , CFR 1.142(b), as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 7/18/2025.
Claims 1, 3, 5-6, 8, 10-11, 19, 136-140 are being examined.
The art rejection and double patenting rejection have been withdrawn as the prior art of record does not specifically teach or suggest, “determining an observed allele frequency for an HLA allele of the HLA gene, wherein the observed allele frequency is experimentally determined based on a ratio of a number of sequence reads for the HLA allele to a total number of sequence reads for the HLA gene; determining a relative binding propensity for the HLA allele to the bait molecule, wherein the relative binding propensity of the HLA allele is experimentally determined based on a ratio of a propensity for binding of a nucleic acid encoding at least a portion of the HLA allele to the bait molecule to propensities for binding of nucleic acids encoding at least portions of one or more other HLA alleles to the bait molecule; applying a quadratic objective function to measure a difference between the relative binding propensity for the HLA allele and the observed allele frequency of the HLA allele ;applying a least squares optimization model to minimize the quadratic objective function; determining an adjusted allele frequency of the HLA allele based on the least squares optimization model and the observed allele frequency of the HLA allele.”
Priority
The instant application was filed 08/25/2022 and is a national stage entry of PCT/US2021/019982 with an international filing date: 02/26/2021 and claims priority from provisional application 63093015 , filed 10/16/2020 and claims Priority from provisional application 62982677 , filed 02/27/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/18/2025 and 6/25/2026 are being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required:
Claim 1 has been amended.to recite, “quadratic objective function.” Review and searching of the specification did not reveal antecedent basis for the limitation.
Claim Rejections - 35 USC § 112
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, 3, 5-6, 8, 10-11, 19, 136-139 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.
Claim 1 has been amended.to recite, “quadratic objective function.” The response asserts support can be found in paragraphs 0066, 0091, 0104, and 0105. This argument has been thoroughly reviewed, but is not considered persuasive as the recited paragraphs do not provide antecedent basis for the limitation. While paragraph 0091 recites, optimization model is quadratic regression, this does not support “quadratic objective function.” Thus the amendment is not supported by the originally filed specification and is new matter.
Response to Arguments
This is a new ground of rejection necessitate by amendment.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3, 5-6, 8, 10-11, 19, 136-140 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.
Claim 1 is indefinite because it lacks a positive active step relating back to the preamble. The preamble recites a method of detecting loss-of-heterozygosity (LOH) of a human leukocyte antigen (HLA) gene, however the last positive active step is drawn to generating a report that comprises one or more treatment options identified for the individual based at least in part on a determination that LOH of the HLA gene has occurred. Therefore it is unclear as to whether the method is drawn to detecting loss-of-heterozygosity (LOH) of a human leukocyte antigen (HLA) gene or generating a report that comprises one or more treatment options identified for the individual based at least in part on a determination that LOH of the HLA gene has occurred.
Claim 1 has been amended to recite, “determining a relative binding propensity for the HLA allele to the bait molecule, wherein the relative binding propensity of the HLA allele is experimentally determined based on a ratio of a propensity for binding of a nucleic acid encoding at least a portion of the HLA allele to the bait molecule to propensities for binding of nucleic acids encoding at least portions of one or more other HLA alleles to the bait molecule;.” The metes and bounds are unclear what is required of “experimentally determined based on a ratio of a propensity for binding of a nucleic acid encoding at least a portion of the HLA allele to the bait molecule to propensities for binding of nucleic acids encoding at least portions of one or more other HLA alleles to the bait molecule” as the claim only require amplifying, capturing, and sequencing. Thus it is unclear how binding propensity is determined.
The claim continues by asserting, “applying a quadratic objective function to measure a difference between the relative binding propensity for the HLA allele and the observed allele frequency of the HLA allele.” The recitation is vague, unclear and incomplete as to how a quadratic objective function is performed.
The claim continues by reciting, “applying a least squares optimization model to minimize the quadratic objective function.” The recitation is vague, unclear and incomplete how this is done.
The claim continues by reciting, “determining an adjusted allele frequency of the HLA allele based on the least squares optimization model and the observed allele frequency of the HLA allele.” The recitation of “the least squares optimization” lacks antecedent basis. Further the metes and bounds are unclear how “least squares optimization model.” Further it is unclear what “based on the least squares optimization model and the observed allele frequency of the HLA allele, “ as based on is not an art accepted term. Thus it is unclear how adjusted HLA frequency is determined.
Claim 1 concludes with, “ generating a report that comprises one or more treatment options identified for the individual based at least in part on a determination that LOH of the HLA gene has occurred.” This is vague, unclear and incomplete how treatment options are determined as the subject is not required to be sick.
Claim 3 recites, “, further comprising, based at least in part on detection of LOH of the HLA gene, administering an effective amount of a treatment other than an immune checkpoint inhibitor (ICI) to the individual.” The metes and bounds are unclear what is required of “based on” as “based on” is not defined by the specification or claim and is not an art accepted term..
Claim 5 recites, “further comprising: detecting, or acquiring knowledge of, a high tumor mutational burden (TMB) in the sample.” The metes and bounds are unclear how “acquiring knowledge of a high tumor mutational burden (TMB) in the sample” is done without detecting mutations in a sample. Further the recitation of “high tumor burden” suggests there is low tumor burden or not so high tumor burden. It is unclear how to differentiate a high tumor burden from other tumor burdens.
Claim 6 recites, “further comprising, based at least in part on detection of LOH of the HLA gene and high TMB, administering an effective amount of an immune checkpoint inhibitor (ICI) to the individual.” The metes and bounds are unclear what is required of “based on” as “based on” is not defined by the specification or claim. Further the recitation of “high tumor burden” suggests there is low tumor burden or not so high tumor burden. It is unclear how to differentiate a high tumor burden from other tumor burdens.
Claim 13 has been added by amendment and recites, “wherein the population of bait molecules comprise one or more bait molecules that target different alleles of the HLA gene with different affinities.” The recitation of “different affinities” suggests there are the same affinities. The specification and claims do not provide a standard to differentiate different affinities from same affinities.
Claim 140 has been amended to recite, “determining a relative binding propensity for the HLA allele to the bait molecule, wherein the relative binding propensity of the HLA allele is experimentally determined based on a ratio of a propensity for binding of a nucleic acid encoding at least a portion of the HLA allele to the bait molecule to propensities for binding of nucleic acids encoding at least portions of one or more other HLA alleles to the bait molecule;.” The metes and bounds are unclear what is required of “experimentally determined based on a ratio of a propensity for binding of a nucleic acid encoding at least a portion of the HLA allele to the bait molecule to propensities for binding of nucleic acids encoding at least portions of one or more other HLA alleles to the bait molecule” as the claim only require amplifying, capturing, and sequencing. Thus it is unclear how binding propensity is determined.
Response to Arguments
The response traverses the previous rejection in view of the amendments. This argument has been thoroughly reviewed but is not considered persuasive as the amendment has introduced new issues.
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 1, 3, 5-6, 8, 10-11, 19, 136-140 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a mental step and/or abstract idea without significantly more. The judicial exception is not integrated into a practical application because the claims do not provide a specific treatment which is dependent on the judicial exceptions. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the active steps are generic and require no specific reagents with account for significantly more.
Claim analysis
The instant claim 1 is directed to A method of detecting loss-of-heterozygosity (LOH) of a human leukocyte antigen (HLA) gene, comprising: providing a plurality of nucleic acids obtained from a sample from an individual, wherein the plurality of nucleic acids comprises nucleic acids encoding an HLA gene;
The steps of :
determining an observed allele frequency for an HLA allele of the HLA gene, wherein the observed allele frequency is experimentally determined based on a ratio of a number of sequence reads for the HLA allele to a total number of sequence reads for the HLA gene;
determining a relative binding propensity for the HLA allele to the bait molecule, wherein the relative binding propensity of the HLA allele is experimentally determined based on a ratio of a propensity for binding of a nucleic acid encoding at least a portion of the HLA allele to the bait molecule to propensities for binding of nucleic acids encoding at least portions of one or more other HLA alleles to the bait molecule; applying a quadratic objective function to measure a difference between the relative binding propensity for the HLA allele and the observed allele frequency of the HLA allele ;
applying a least squares optimization model to minimize the quadratic objective function; determining an adjusted allele frequency of the HLA allele based on the least squares optimization model and the observed allele frequency of the HLA allele;
determining that LOH has occurred when the adjusted allele frequency of the HLA allele is less than a predetermined threshold; and
generating a report that comprises one or more treatment options identified for the individual based at least in part on a determination that LOH of the HLA gene has occurred
are mental steps and abstract ideas..
Claim 140 is drawn to A method of detecting loss-of-heterozygosity (LOH) of a human leukocyte antigen (HLA) gene, comprising: providing a plurality of nucleic acids obtained from a sample from an individual, wherein the plurality of nucleic acids comprises nucleic acids encoding an HLA gene; amplifying nucleic acids from the plurality of nucleic acids; capturing a plurality of nucleic acids corresponding to the HLA gene, wherein the plurality of nucleic acids corresponding to the HLA gene is captured from the amplified nucleic acids by hybridization with a bait molecule of a population of bait molecules targeting the HLA gene; sequencing, by a sequencer, the captured nucleic acids to obtain a plurality of sequence reads corresponding to the HLA gene; determining an observed allele frequency for an HLA allele of the HLA gene, wherein the observed allele frequency is determined based on a ratio of a number of sequence reads for the HLA allele to a total number of sequence reads for the HLA gene; determining a relative binding propensity for the HLA allele to the bait molecule, wherein the relative binding propensity of the HLA allele is determined based on a ratio of a propensity for binding of a nucleic acid encoding at least a portion of the HLA allele to the bait molecule to propensities for binding of nucleic acids encoding at least portions of one or more other HLA alleles to the bait molecule; determining an adjusted allele frequency of the HLA allele based on the observed allele frequency of the HLA allele; and determining that LOH has occurred when the adjusted allele frequency of the HLA allele is less than a predetermined threshold.
The steps of
determining an observed allele frequency for an HLA allele of the HLA gene, wherein the observed allele frequency is determined based on a ratio of a number of sequence reads for the HLA allele to a total number of sequence reads for the HLA gene; determining a relative binding propensity for the HLA allele to the bait molecule, wherein the relative binding propensity of the HLA allele is determined based on a ratio of a propensity for binding of a nucleic acid encoding at least a portion of the HLA allele to the bait molecule to propensities for binding of nucleic acids encoding at least portions of one or more other HLA alleles to the bait molecule;
determining an adjusted allele frequency of the HLA allele based on the observed allele frequency of the HLA allele; and
determining that LOH has occurred when the adjusted allele frequency of the HLA allele is less than a predetermined threshold.
are mental steps and abstract ideas.
The providing, ligating, amplifying, capturing, and sequencing are considered to be an active step requiring the analysis of a sample.
Claim 3 requires a treatment other than ICI, which is general and not specific.
Claim 5 provides the mental steps of acquiring tumor burden data.
Claim 6 recites, “based at least in part on detection of LOH of the HLA gene and high TMB, administering an effective amount of an immune checkpoint inhibitor (ICI) to the individual.” The recitation of based at least in part demonstrates the claim is not limited to applying a judicial exception.
Claim 8 limits the HLA gene.
Claim 10-11 limit the sample.
Claim 19 provides the mental step or abstract idea how tumor burden is calculated.
Claim 137 limits the bait molecules comprise one or more bait molecules that target different alleles.
Claims 138-139 provide treatment options. However, the claims do not require treatment. Thus these further limit mental steps, but are not significantly more.
According to the 2019 Patent Eligibility Guidance an initial two step analysis is required for determining statutory eligibility.
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter? In the instant case the Step 1 requirement is satisfied as the claims are directed towards a process.
Step 2A Prong one. Does the claim recite a law of nature, a natural phenomenon or an abstract idea? Yes, abstract idea.
With regards to claim 1, the claim recites,
determining an observed allele frequency for an HLA allele of the HLA gene, wherein the observed allele frequency is experimentally determined based on a ratio of a number of sequence reads for the HLA allele to a total number of sequence reads for the HLA gene;
determining a relative binding propensity for the HLA allele to the bait molecule, wherein the relative binding propensity of the HLA allele is experimentally determined based on a ratio of a propensity for binding of a nucleic acid encoding at least a portion of the HLA allele to the bait molecule to propensities for binding of nucleic acids encoding at least portions of one or more other HLA alleles to the bait molecule; applying a quadratic objective function to measure a difference between the relative binding propensity for the HLA allele and the observed allele frequency of the HLA allele ;
applying a least squares optimization model to minimize the quadratic objective function; determining an adjusted allele frequency of the HLA allele based on the least squares optimization model and the observed allele frequency of the HLA allele;
determining that LOH has occurred when the adjusted allele frequency of the HLA allele is less than a predetermined threshold; and
generating a report that comprises one or more treatment options identified for the individual based at least in part on a determination that LOH of the HLA gene has occurred
These are mathematical concepts, abstract ideas or mental steps..
Further claim 140 recites:
determining an observed allele frequency for an HLA allele of the HLA gene, wherein the observed allele frequency is determined based on a ratio of a number of sequence reads for the HLA allele to a total number of sequence reads for the HLA gene; determining a relative binding propensity for the HLA allele to the bait molecule, wherein the relative binding propensity of the HLA allele is determined based on a ratio of a propensity for binding of a nucleic acid encoding at least a portion of the HLA allele to the bait molecule to propensities for binding of nucleic acids encoding at least portions of one or more other HLA alleles to the bait molecule;
determining an adjusted allele frequency of the HLA allele based on the observed allele frequency of the HLA allele; and
determining that LOH has occurred when the adjusted allele frequency of the HLA allele is less than a predetermined threshold.
These are mathematical concepts, abstract ideas or mental steps.
Step 2A prong two. Does the claim recite additional elements that integrate the judicial exception into a practical application? The answer is no the claim requires no additional steps which are dependent on the judicial exception in a way which integrates the judicial exception.
Step 2B. Does the claim recite additional elements that are significantly more than the judicial exceptions? No, the claim provides no specific steps which require specific reagents, which could be significantly more.
The active steps of claim 1 and 140 are routine and conventional in view of Swanton (Wo2019/012296), Chalmers (US20180363066). Further Murphy (Molecular Genetics & Genomic Medicine 2014; 2(3): 245–253) teaches allele specific HLA capture probes (baits).
Response to Arguments
The response traverses the rejection by arguing the active steps of the claims cannot be done in the mind. This argument has been thoroughly reviewed but is not considered persuasive as the rejection indicates the active steps are routine and conventional. Thus the arguments are inconsistent with the rejection.
The response continues by asserting the independent claim provides a technical improvement and solves challenges in the filed of cancer diagnostics and treatment. This argument has been thoroughly reviewed but is not considered persuasive as the claims are not limited to cancer treatment. Thus the argument is not commensurate in scope with the claimed invention. Further the claim does not integrate the judicial exception as the generating a report is providing a summary of what was identified and instructions on how to apply the findings, but lacks any specificity or treatment.
The response continues providing arguments on the bottom of page 12 by conceding the method uses a statistical modeling approach. Thus the response concedes the claim is drawn to mathematical concepts, abstract ideas or mental steps.
The response continues by asserting, “Because of the heterogeneity of the HLA gene, standard targeted sequencing processes cannot be used to accurately determine the allele frequency for a given HLA allele due to differences in the relative binding affinities between the bait molecule used to target the HLA gene and different HLA alleles. In the claimed method, the experimentally-determined observed allele frequency (based on sequence read counts that map to the HLA allele) is adjusted using a statistical modeling approach to account for differences in the relative binding of one or more bait molecules to different HLA alleles. The binding of physical nucleic acid molecules to physical bait molecules is observed and quantified.” This argument has been thoroughly reviewed but is not considered persuasive as while the claims encompasses this the claims do not specifically require this. Further these are arguments of counsel that have not been substantiated by evidence.
The response traverses the rejection in view of the generating step. The step of generating a report is providing a summary of what was identified and is a mental step and/or instructions on how to apply the findings. Thus it is not significantly more.
Summary
No claims are allowed.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEVEN C POHNERT PhD whose telephone number is (571)272-3803. The examiner can normally be reached Monday- Friday about 6:00 AM-5:00 PM, every second Friday off.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Anne Gussow can be reached at (571)272-6047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Steven Pohnert/Primary Examiner, Art Unit 1683
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