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 .
The amended claims dated 6/23/2026 are under consideration.
Election/Restrictions
Applicant’s election without traverse of the combination of species LILRB4 and CISH in the reply filed on 6/23/2023 is acknowledged.
Claims 4, 5, 6, 7, 11, 12, 15, 18, 19, 20, 21, 27 and 28 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 6/23/2023. The withdrawn claims require assessing combinations of genes that include unelected species.
Priority
The present application claims benefit of 63/382,972 (filed 11/9/2022) and 63/503,946 (filed 5/23/2023).
The ‘972 provisional application does not disclose CISH as a transcript or that LILRB4 is an elevated transcript. Both are elements of claim 1. Because the ‘972 provisional application fails to disclose these elements priority is not recognized.
The application is given the earliest effective filing date of 5/23/2023, the filing date of the ‘946 provisional application.
Information Disclosure Statement
The listing of references in the specification or the citation of references throughout 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 or cited on a submitted IDS, they have not been considered.
Drawings
A petition for colored drawings was filed on 11/8/2023 and was granted on 1/3/2024.
Specification
The use trade names or marks used in commerce has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 1 is objected to because of the following informalities: the claim recites “an immune-related adverse events” rather than “an immune-related adverse event” or “immune-related adverse events”. Appropriate correction is required.
Claim 1 is objected to because of the following informalities: the claim recites “in the subject wherein, the subject” rather than “in the subject, wherein the subject”. Appropriate correction is required.
Claim Interpretation
In claim 1, the steps of “assessing” and “predicting” read on intangible actions, such as the abstract ideas of processing and thinking about transcript levels. The steps are integrated into a practical application by the “treating” step of the claim.
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, 2, 3, 8, 9, 10, 13, 14 and 16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
The specification, while being enabling for:
methods that in part require: providing a PBMC sample from a subject with lung cancer, pancreatic cancer or melonoma; predicting a risk of myocarditis and/or myositis to PD-1 or PD-L1 ICI; and treating a patient in view of their predicted risk of myocarditis and/or myositis,
does not reasonably provide enablement for
methods that in part require: providing any sample from any subject with any condition; predicting a risk of any immune-related adverse event to any ICI; and treating a patient in view of their predicted risk of any immune-related adverse event.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
Claim 1 broadly encompasses providing any sample from any subject. The sample broadly encompasses blood, saliva, serum, plasma, urine, any tissue, etc. The subject broadly encompasses any subject having any disease being treated with any ICI. Claim 1 broadly encompasses predicting any immune-related adverse events.
The instant specification only provided PBMC samples for assessing transcript levels (para. 420). The only immune-related adverse events were myocarditis and/or myositis (Table 4). The only ICI treatments analyzed was PD-1 and PD-L1 (Table 2).
It is understood in the field that different types of cells and tissues express transcripts at different levels. Saito-Hisaminato (DNA Research. 2002. 9:35-45) demonstrates that transcript levels vary between tissues and cells. Thus, one would not reasonably expect that the PBMC transcript levels observed by applicant may be extrapolated to all types of samples. PBMC are largely cells of the immune system, and genes such as LILRB4, CISH and CXCL8 are genes relevant to cells of the immune system. Tissues and samples lacking these immune cells are not likely to provide transcript levels that are informative in terms of making predictions regarding the risk of immune-related adverse events.
Similarly to tissues and cells, conditions have different expression patterns of transcripts based on the organs, tissues or cells impacted by the condition. Thus, one would not have reasonably found that the results from patients with melanoma, pancreas and lung cancers may be reasonably extrapolated to all other types of conditions and/or diseases.
ICI treatments are known and target different pathways. CTLA-4 is thought to target cells in the lymph nodes while PD-1 acts in peripheral tissues. The signaling pathways of each result in different downstream effects. See Buchbinder (Am J Clin Oncol. 2016. 39:98-106). One would not reasonably predict that the transcript levels informative in the context of the PD-1 and PD-L1 blocking are equally applicable to predicting immune-related adverse effects to CTLA-4 treatment because of the different mechanisms of action.
Adverse events resulting from CTLA-4, PD-1 and PD-L1 differ. See Buchbinder (Am J Clin Oncol. 2016. 39:98-106). Thus, one would not reasonably predict that the transcript levels predictive of myocarditis and/or myositis may be extrapolated to other adverse events, such as rash, pruritus and endocrinopathies.
For the reasons provided above, the claims are not fully enabled.
Claim Rejections - 35 USC § 112
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, 2, 3, 8, 9, 10, 13, 14 and 16 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.
Regarding claim 1, the claim generically recites “assessing the level of one or more transcripts in the sample”. The “predicting” step is based on the transcript levels of specific genes, such as LILRB4 and/or CISH. There is a gap between the “assessing” step and the “predicting” step in that the “predicting” step is based in part on transcript levels that are not necessarily assessed in the claimed method. It is unclear if the “assessing” step is intended to specifically assess the transcript levels of one or more of LILRB4, CISH, AREG, CXCL8, ERG1, PAX8 and ATF6B.
Claims 2, 3, 8, 9, 10, 13, 14 and 16 depend from claim 1 and are rejected for the same reason.
Regarding claim 16, the claim generically recites “assessing the level of one or more transcripts in the sample”. The “predicting” step is based on the transcript levels of specific genes, such as LILRB4 and/or CISH. There is a gap between the “assessing” step and the “predicting” step in that the “predicting” step is based in part on transcript levels that are not necessarily assessed in the claimed method. It is unclear if the “assessing” step is intended to specifically assess the transcript levels of one or more of LILRB4, CISH, AREG, CXCL8, ERG1, PAX8 and ATF6B.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 3, 8, 9, 10, 14 and 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Friedlander (Journal for ImmunoTherapy of Cancer. 2018. 6:90, 12 pages and Table S2).
The following are rejections over non-elected species.
Regarding claims 1, 8, 9 and 16, Friedlander teaches providing a sample from a subject in the form of whole blood (p. 3 of 12, Whole-blood gene expression profiling).
Friedlander teaches assessing the level of one or more transcripts in the blood using PCR (p. 3 of 12, Whole-blood gene expression profiling).
Friedlander teaches predicting a patient will have diarrhea as an immune-related adverse event in response to treatment with tremelimumab based on transcript levels. The transcript levels included IL8/CXCL8 (Table 2) and ERG1 (Table S2). The patients had lower levels of IL8 in Grade 2-4 versus Grade 0-1 as a control and lower pretreatment versus post treatment (Table 2). ERG1 had similar trends as depicted in Table S2.
It would have been prima facie obvious to have treated a patient with a something other than tremelimumab if they are predicted to develop diarrhea or to have continued to treat the patient with tremelimumab if they are predicted to not develop diarrhea.
Regarding claim 3, Friedlander teaches determining transcript levels prior to treatment (Table 2).
Regarding claim 10, Friedlander teaches the transcript levels are “relative” as they have been normalized (p. 3 of 12, Whole-blood gene expression profiling).
Regarding claim 14, Friedlander teaches samples and transcript levels from different time points (p. 3 of 12, Whole-blood gene expression profiling; and Table 2).
Improper Markush
Claims 1, 2, 3, 8, 9, 10, 13, 14 and 16 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 706.03(y).
The claims recite the following Markush grouping: the genes recited in the “predicting” step. The Markush group is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
It is first noted that MPEP 706.03(y) states that “A Markush claim may be rejected under judicially approved “improper Markush grouping” principles when the claim contains an improper grouping of alternatively useable members. A Markush claim contains an “improper Markush grouping” if either: (1) the members of the Markush group do not share a “single structural similarity” or (2) the members do not share a common use. Supplementary Guidelines at 7166 (citing In re Harnisch, 631 F.2d 716, 721-22, 206 USPQ 300, 305 (CCPA 1980)). “ Members of a Markush group share a “single structural similarity” when they belong to the same recognized physical or chemical class or to the same art-recognized class (prong 1) and the members of a Markush group share a common function or use when they are disclosed in the specification or known in the art to be functionally equivalent (prong 2).
The phrase “significant structural element is shared by all of the alternatives” refers to cases where the compounds share a common chemical structure which occupies a large portion of their structures, or in case the compounds have in common only a small portion of their structures, the commonly shared structure constitutes a structurally distinctive portion in view of existing prior art, and the common structure is essential to the common property or activity.
A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein “there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved” (see MPEP 706.03(y)IIA).
Here, the recited alternative species do not share a single structural similarity, as each gene has a different chemical structure in that it consists of a different nucleotide sequence and encodes a protein with a different structure and function. The only structural similarity present is that all of the genes comprise nucleotides or all the proteins comprise amino acid. The fact that the genes comprise nucleotides or proteins comprise amino acids per se does not support a conclusion that they have a common single structural similarity because the structure of comprising nucleotides or amino acids alone is not essential to the asserted common activity of being correlated with a prediction. Accordingly, while the different genes are asserted to have the property of being correlated with risk prediction, they do not share a substantial structural similarity essential to this activity.
Further, the recited genes do not belong to a chemical or art-recognized class because there is no expectation from the knowledge in the prior art that genes behave in the same manner and can be substituted for one another with the same intended result achieved. The genes are different classes as LILRB4 is an inhibitory receptor on antigen presenting cells, CISH modulates TCR signaling in T cells, AREG is a growth factor receptor and CXCL8 is a pro-inflammatory chemokine. There is no evidence of record to establish that it is clear from their very nature that the recited genes possess the common property of being correlated with a risk prediction.
Following this analysis, the claims are rejected as containing an improper Markush grouping.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH G DAUNER whose telephone number is (571)270-3574. The examiner can normally be reached 7 am EST to 4:30 EST with second Fridays Off.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Winston Shen can be reached at 5712723157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JOSEPH G. DAUNER/Primary Examiner, Art Unit 1682
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