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 .
Election/Restrictions
Applicant’s election without traverse of i) the combination of genes: IFNGR2, MICB, MICA, STAT6, IFIT1, IFIT2, IFIT3, IFNGR1, IL16, STAT4, STAT5A, STAT2, SOCS5, STAT3, TNFSF4, ES, CD86, HAVCR2, LAG3, PDCD1, TBX21, TNFRSF14, IDO1, PDCD1LG2, and CD47; ii) nucleic acid analysis; iii) antibody; and iv) tumor biopsy in the reply filed on 9/3/2025 is acknowledged. Since claims 1 and 11 require that the expression of all genes in the claims be assessed, and this combination comprises the elected combination. combination of all genes from claims 1 and 11 is rejoined with the elected combination of genes.
Claims 1-5, 7, 9, 11-15, 17, 19, and 21-25 are examined herein. Claims 6, 8, 10, 16, 18, 20, and 26 are withdrawn from consideration as being directed to non-elected species.
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 11-15, 17, 19, and 21-25 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural correlation/law of nature and an abstract idea without significantly more. This judicial exception is not integrated into a practical application and the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons set forth below.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106. The unpatentability of abstract ideas was confirmed by the U.S. Supreme court in Bilski v. Kappos, 561 U.S. 593, 601 (June 28, 2010) and Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 134 S. Ct. 2347, 2354 (2014). See also Myriad v Ambry, CAFC 2014-1361, -1366, December 17, 2014. The unpatentability of laws of nature was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. 66, 71 (2012). “[L]aws of nature, natural phenomena, and abstract ideas” are not patentable. Dia-mond v. Diehr, 450 U. S. 175, 185 (1981); see also Bilski v. Kappos, 561 U. S. at 601 (2010).
Claims Analysis:
As set forth in MPEP 2106, the claims have been analyzed to determine whether they are directed to one of the four statutory categories (STEP 1).
The instant claims are directed to methods and therefore are directed to one of the four statutory categories of invention.
The claims are then analyzed to determine if they recite a judicial exception (JE) (STEP 2A, prong 1) [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)].
The claimed invention recites a method of “selecting subjects for [a] clinical trial” and “processing or analyzing a a biological sample from a NSCLC subject” by assessing gene expression of some or all of the genes listed in the claims and determining responsiveness to immunotherapy using the gene expression. However, this recitation is a natural correlation between expression levels of genes and immunotherapy efficacy. With regard to the natural correlation, as in Mayo, the relationship is itself a natural process that exists apart from any human action. The claimed invention also recites steps such as “determining that the NSCLC is responsive”, “selecting subjects”, and “using an algorithm in a computer to process data” which are directed to abstract ideas because they encompass conclusions and determinations which can occur entirely within the mind. It is therefore determined that the claims are directed to judicial exceptions.
The claims are then analyzed to determine whether they recite an element or step that integrates the JE into a practical application (STEP 2A, prong 2) [Vanda Pharmaceuticals Inc., v. West-Ward Pharmaceuticals, 887 F.3d 1117 (Fed. Cir. 2018)].
The claims recite require steps of measuring gene expression of combinations of genes, however this does not integrate the JE into a practical application because it is a mere data gathering step to use the correlation and does not add a meaningful limitation to the method. Although claim 11 recites “administering an immunotherapy”, this appears to be for the purposes of analyzing responsiveness to immunotherapy rather than a step which practically applies the natural correlation. The step of “electronically outputting a report” in claim 21 does not practically apply the JE because it simply recites the result of the analysis which is the JE itself. Furthermore, “seeking regulatory approval” is a legal action rather than a practical application of the natural correlation recited in the JE. Furthermore, it is taken as a general “apply it” step. The Supreme Court does acknowledge that it is possible to transform an unpatentable law of nature, but one must do more than simply state the law of nature while adding the words "apply it.” CLS BankInt’l, 134 S.Ct. at 2358; Prometheus, 132 S. Cl, at 1294.
In the absence of steps or elements that integrate the JE into a practical application, the additional elements/steps are considered to determine whether they add significantly more to the JE either individually or as an ordered combination, to “’transform the nature of the claim’ into a patent eligible application” [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)] (STEP 2B).
In the instant situation, the step of obtaining a sample or nucleic acids is considered insignificant post solution activity. The steps of measuring expression levels are generally recited and do not provide any particular reagents that might be considered elements that transform the nature of the claims into a patent eligible application because no specific elements/steps are recited. This step is not only a mere data gathering step, but the general recitation of detection of known nucleic acids is well understood, routine, and conventional activity (See MPEP 2106.05(d)(II)). Applicant is reminded that in Mayo, the Court found that “[i]f a law of nature is not patentable, then neither is a process reciting a law of nature, unless that process has additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself." Further "conventional or obvious" "[pre]solution activity" is normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such a law”. Flook, 437 U. S., at 590; see also Bilski, 561 U. S., at ___ (slip op., at 14) (“[T]he prohibition against patenting abstract ideas ‘cannot be circumvented by’ . . . adding ‘insignificant post-solution activity’” (quoting Diehr, supra, at 191–192)). The Court also summarized their holding by stating “[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.” Therefore, these limitations/steps do not “‘transform the nature of the claim’ into a patent-eligible application.’” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
When viewed as an ordered combination, the claimed limitations are directed to nothing more than the determination that a natural correlation/phenomenon exists. Any additional element consists of using well understood, routine and conventional activity, and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.
Accordingly, it is determined that the instant claims are not directed to patent eligible subject matter.
Claim Rejections - 35 USC § 112
112(a)
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.
Claims 1-5, 7, 9, 11-15, 17, 19, and 21-25 are rejected under 35 U.S.C. 112(a) as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. There are many factors to be considered when determining whether there is sufficient evidence to support determination that a disclosure does not satisfy the enablement requirements and whether any necessary experimentation is undue. These factors have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.”
The nature of the invention and the breadth of the claims:
The claims are directed to methods of determining responsiveness of NSCLC in a patient to broadly any immunotherapy by measuring expression of the genes listed in the claims. The claims recite that broadly any “fifteen or more of the genes associated with immune activation” and “10 or less of the genes associated with immune inhibition” are upregulated as a determination that the NSCLC is responsive to immunotherapy.
It is noted, however, the identity of some of the genes listed in the claims are not clear. At para 0049, the specification provides examples of accession numbers for some of the genes, however it is not clear if the claims are limited to these accession numbers or encompass variants of the recited genes. Additionally, the specification does not clarify the identify for CD28, CD40, “4-1BB”, GITR, CD27, ICOS, CD226, B7, TCR, CD40L, CTLA4, PD1, TIM2, BTLA, TIGIT, CD96, H3, VISTA, or CD112R at para 0049. While some of the acronyms for these genes are art accepted, others are confusing. For example, 4-1BB appears to be an alias for TNFRSF9, however it is not clear why the claim recites both in the list. The identity of the genes designated as B7, ES, H3, TCR, and VISTA, for example, are not clear as there appear to be multiple genes with aliases that contain one or all of the letter/number acronyms. For example , does B7 refer to B7-H1? Which gene is considered to be “H3” or “VISTA”? Additionally, GITR is listed in both the “immune activation” and “immune inhibition” gene groups in claims 1 and 11, however the claims require assessment of efficacy using “fifteen or more” of the immune activation set and “10 or less” of the immune inhibition set. Given that GITR is listed in both sets, it is not clear how it’s expression should be evaluated to determine that and NSCLC is responsive to immunotherapy.
The invention is in a class of inventions which the CAFC has characterized as 'the unpredictable arts such as chemistry and biology" (Mycolgen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Federal Circuit 2001)).
The amount of direction or guidance and Presence and absence of working examples:
The specification teaches that RNA seq was conducted on samples using a panel of “500 immune related genes” (para 0114). However the panel does not appear to be identified by the specification, as such the identity of the specific genes whose expression was measured cannot be ascertained. The specification teaches that hierarchical clustering of the RNA seq data revealed that NSCLC samples clustered into two overall groups, CD 8 high and CD8 low tissues, however it also notes that a CD8 moderate samples were also present. The specification states that the clustering analysis revealed a gene expression signature that may correlate with tissues that are CD8 high or low. The specification teaches that specific tissues were analyzed and that expression analysis revealed different patterns of expression of genes associated with immune activation and immune inhibition. However, the specification does not teach or provide any guidance as to which immunotherapy these genes might be predictive of, or what the actual genes in each tissue sample were. The specification does not provide any guidance as to which 15 or more, or 10 or less genes from those listed in the claims are predictive of immunotherapy response or how these cutoffs were determined. The specification is also silent as to which immunotherapies would be predicted to be efficacious in patients with NSCLC simply based on gene expression profiling.
The state of the prior art and the predictability or unpredictability of the art:
The prior art confirms the variability and lack of consensus in gene signatures identified through gene expression profiling that may or may not be associated with immunotherapy efficacy in NSCLC. Jamieson (Jamieson and Maker; Cancer Gene Therapy, vol 24, pages 1-15; 2017) teaches of several studies that identified different gene expression signatures as prognostic of survival in patients treated with atezolizumab (see page 3). Jamieson also teaches that other clinical trials have found no difference in outcome based on gene expression profiles. Jamieson teaches that these results support that immunological responses to vaccines may not translate to clinical response, and highlights the difficulty and complexity in creation of predictive gene signatures using gene expression profiling in trials with different immunotherapy drugs and amongst different tumor types.
The level of skill in the art:
The level of skill in the art is deemed to be high.
The quantity of experimentation necessary:
While the state of the art and level of skill in the art with regard to the general measurement of gene expression is high, the level of unpredictability in associating gene expression with particular phenotypes is even higher. To practice the invention as broadly as it is claimed, the skilled artisan would be required to conduct an enormous amount of trial and error experimentation to arrive at particular gene signatures and gene expression levels which are associated with efficacy of different types of immunotherapy to NSCLC tumors. Thus given the broad claims in an art whose nature is identified as unpredictable, the unpredictability of that art, the large quantity of research required to define these unpredictable variables, the lack of guidance provided in the specification, the absence of a working example and the negative teachings in the prior art balanced only against the high skill level in the art, it is the position of the examiner that it would require undue experimentation for one of skill in the art to perform the method of the claim as broadly written.
112(b)
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.
Claims 1-5, 7, 9, 11-15, 17, 19, and 21-25 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
The claims require measuring expression levels of particular genes. However, the identity of some of the genes are not clear. At para 0049, the specification provides examples of accession numbers for some of the genes, however it is not clear if the claims are limited to these accession numbers or encompass variants of the recited genes. Additionally, the specification does not clarify the identify for CD28, CD40, “4-1BB”, GITR, CD27, ICOS, CD226, B7, TCR, CD40L, CTLA4, PD1, TIM2, BTLA, TIGIT, CD96, H3, VISTA, or CD112R at para 0049. While some of the acronyms for these genes are art accepted, others are confusing. For example, 4-1BB appears to be an alias for TNFRSF9, however it is not clear why the claim recites both in the list. The identity of the genes designated as B7, ES, H3, TCR, and VISTA, for example, are not clear as there appear to be multiple genes with aliases that contain one or all of the letter/number acronyms. For example , does B7 refer to B7-H1? Which gene is considered to be “H3” or “VISTA”?
The recitation of CD226 occurs twice, however it is not clear if this a typographical error. GITR is listed in both the “immune activation” and “immune inhibition” gene groups in claims 1 and 11, however the claims require assessment of efficacy using “fifteen or more” of the immune activation set and “10 or less” of the immune inhibition set. Given that GITR is listed in both sets, it is not clear how it’s expression should be evaluated to determine that and NSCLC is responsive to immunotherapy.
The preamble of claim 11 recites “conducting a clinical trial by selecting subjects” however the last active process step recites “seeking regulatory approval for the immunotherapy”. Accordingly, the metes and bounds of the method are unclear. Additionally, the claim recites “administering an immunotherapy to the subject where the subject is determined to be responsive to the immunotherapy”, however it is not clear if further assessment of immunotherapy responsiveness follows this step or not.
The term “upregulated” is a relative term which renders the claim indefinite. The term is not defined by the claim, and the specification does not provide a standard for ascertaining the requisite degree. Therefore, absent an indication as to what particular reference it is being compared to, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 21-25 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Prat (Prat et al; Cancer Research, vol 77, July 2017; pages 3540-3550).
Claim 21 does not require that sequencing of all of the genes listed in the claims be conducted, but rather “one or more” of the genes. Accordingly, claim 21 has been given its broadest reasonable interpretation to encompass sequence to yield data of gene expression signatures that comprise less than all of the genes listed in the claim.
Prat teaches immune related gene expression profiling in NSCLC for patients treated with with pembrolizumab or nivolumab (claims 22-25) (see page 3542, col 1: “All patients had been recruited in various clinical trials evaluating the efficacy of anti-PD1 monotherapy [nivolumab…pembrolizumab…]”). With regard to claim 21, Prat teaches evaluating gene expression from NSCLC samples to yield data comprising levels of gene expression products of genes including PD1 and CTLA4 (figure 1), using the genes evaluated on the nCounter platform to derive a gene expression based predicator in a TCGA dataset (page 3543, col 2) and apply it to an nCounter dataset, and report that CD8 T cells and PD1 showed a clear tendency for being associated with ORR, and that 14 signatures together with PD1 and CTLA4 were significantly associated with NPD (page 3545, col 1). It is noted that the publication of the reference is considered “electronically outputting a report”. Accordingly, the teachings of Prat anticipate the instantly rejected claims.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to examiner Jehanne Sitton whose telephone number is (571) 272-0752. The examiner is a hoteling examiner and can normally be reached Mondays-Fridays from 8:00 AM to 2:00 PM Eastern Time Zone.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Winston Shen, can be reached on (571) 272-3157. The fax phone number for organization where this application or proceeding is assigned is (571) 273-8300.
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/JEHANNE S SITTON/Primary Examiner, Art Unit 1682