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 Group I, the combination of SERPINE1, TGFB1, MMP10, LAMC2, PDPN, LAMA3, TNC, LAMB3, and SNAIL2, as well as genes/RNA sequencing in the reply filed on 6/18/2026 is acknowledged.
Claims 49-51 are withdrawn from consideration as being directed to a non-elected invention.
An action on the merits of claims 1-4, 9-12, 17, 19, 20, 41, 42, and 45-48 is set forth herein.
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 1-4, 9-12, 17, 19, 20, 41, 42, and 45-48 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 methods of determining a subject that has a high or low risk of death, recurrence, or metastasis of an epithelial caner by detecting expression of a “p-EMT gene signature”. However, the relationship between the expression levels of the recited genes and the cell types detected is a natural correlation. 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 risk”, “determining average expression levels”, comparing average expression levels” which are directed to abstract ideas because they encompass making decisions, drawing conclusions, and mathematical concepts. 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 steps of determining 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 the claims recite administering steps, the treatments are broadly recited and do not set forth the therapeutics with any level of particularity with regard to epithelial cancer so that they are merely instructions to “apply” the exception in a generic way. The MPEP at 2106.04(d)(2) also explicitly states:
a. The Particularity Or Generality Of The Treatment Or Prophylaxis
The treatment or prophylaxis limitation must be "particular," i.e., specifically identified so that it does not encompass all applications of the judicial exception(s). For example, consider a claim that recites mentally analyzing information to identify if a patient has a genotype associated with poor metabolism of beta blocker medications. This falls within the mental process grouping of abstract ideas enumerated in MPEP § 2106.04(a). The claim also recites "administering a lower than normal dosage of a beta blocker medication to a patient identified as having the poor metabolizer genotype." This administration step is particular, and it integrates the mental analysis step into a practical application. Conversely, consider a claim that recites the same abstract idea and "administering a suitable medication to a patient." This administration step is not particular, and is instead merely instructions to "apply" the exception in a generic way. Thus, the administration step does not integrate the mental analysis step into a practical application.
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 steps of determining expression levels 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/phenomena 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 § 103
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.
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.
Claims 1-4, 9-11, 17, 19, 20, 41, 42, 45-48 are rejected under 35 U.S.C. 103 as being unpatentable over Kan (Kan et al; US 2012/0302572; cited in the IDS filed 4/9/2024) in view of Califano (Califano et al; 20150126374).
Kan teaches a method of treating an epithelial cancer (Abstract 'The present invention provides diagnostic methods for assessing the EMT status of tumor cells, and for predicting the effectiveness of treatment of a cancer patient with an EGFR or IGF-1R kinase inhibitor, utilizing an EMT gene signature index score. The present invention further provides methods for treating patients with cancer that incorporate these methods') comprising: determining whether a subject suffering from an epithelial cancer belongs to a high or low risk group (Claim 49 'determining if said EMTGS index score is more similar to an EMTGS index score from a reference epithelial tumor cell or an EMTGS index score from a reference mesenchymal-like tumor cell, and thus determining the EMT status of the sample tumor cells.'; para [0246] - 'determine if a subject is suffering from or is at increased risk of developing a tumor that is less susceptible to inhibition by an EGFR kinase inhibitor or an IGF-1R kinase inhibitor") by: detecting an average expression of one or more partial EMT-like (p-EMT) signature genes or polypeptides in malignant cells from the subject, wherein the one or more p-EMT signature genes or polypeptides are selected from the group consisting of SERPINE1, TGF81, MMP10, LAMC2, P4HA2, PDPN, ITGA5, LAMA3, CH13, TNC, MMP2, EMP 3, INHBA, LAMB3, SNAIL2, and VIM (:A method of determining the EMT status of tumor cells, comprising measuring in a sample of the tumor cells the relative expression level of each gene of an EMT gene signature ITGA5, SERPINE1, VIM, para [0398]; “To determine whether an index score for a given gene list is significantly different than a score for a random gene list, a method was developed that compares the calculated index score to the average index score from 1000 random gene lists (Significance assessment via randomized re-sampling or "bootstrapping method")." and comparing the average expression of the subject p-EMT signature genes or polypeptides to a control average expression of the p-EMT signature genes or polypeptides for malignant cells obtained from a plurality of subjects having the epithelial cancer and if the subject is in a low risk group, then treating the subject with a treatment that comprises immunotherapy, neoadjuvant therapy and/or chemoradiation (para [0294] “Agents capable of enhancing antitumor immune responses include, for example: CTLA4 (cytotoxic lymphocyte antigen 4) antibodies (e.g. MDX- CTLA4, ipilimumab, MDX-010), and other agents capable of blocking CTLA4. Specific CTLA4 antibodies that can be used in the present invention include those described in U.S. Pat. No. 6,682,736.”); if the subject is in a high risk group, then treating the subject with a treatment that comprises lymph node dissection, adjuvant chemotherapy, adjuvant radiation or post-operative radiation treatment (PORT), chemoradiation, administering an agent that inhibits TGF beta signaling; and/or administering one or more agents targeting malignant cells expressing a p-EMT signature, optionally, further comprising treating the subject with immunotherapy, neoadjuvant therapy and/or chemoradiation (para [0248] – “The present invention further provides any of the methods disclosed herein for treating cancer, or tumors or tumor metastasis in a patient with cancer, comprising administering to the patient a therapeutically effective amount of an EGFR kinase inhibitor or an IGF-1R kinase inhibitor and in addition, simultaneously or sequentially, one or more other cytotoxic, chemotherapeutic or anti-cancer agents, or compounds that enhance the effects of such agents. In the context of this invention, other anti-cancer agents includes, for example, other cytotoxic, chemotherapeutic or anti-cancer agents, or compounds that enhance the effects of such agents, anti-hormonal agents, angiogenesis inhibitors, agents that inhibit or reverse EMT (e.g. TGF-beta receptor inhibitors), anti-proliferative agents, anti-HER2 antibody (e.g. trastuzumab …) or an immunotherapeutically active fragment thereof, anti-proliferative agents, COX II…inhibitors, and agents capable of enhancing antitumor immune responses”; para [0294] “Radiation therapy is a standard treatment for controlling unresectable or inoperable tumors and/or tumor metastases. Improved results have been seen when radiation therapy has been combined with chemotherapy. Radiation therapy is based on the principle that high-dose radiation delivered to a target area will result in the death of reproductive cells in both tumor and normal tissues. In a preferred embodiment of this invention there is synergy when tumors in human patients are treated with the combination treatment of the invention and radiation. In other words, the inhibition of tumor growth by means of the agents comprising the combination of the invention is enhanced when combined with radiation, optionally with additional chemotherapeutic or anti-cancer agents.”)
Kan does not teach wherein the subject is in a high risk group if the average expression in the subject is higher than the control average expression, and the subject is in the low risk group if the average expression in the subject is lower than the control average expression. However since Kan teaches comparing gene expression level between tumor and control groups (para [0030] 'FIG. 8:Summary of EMT morphologic, marker and phenotypic changes and corresponding changes to erlotinib sensitivity and EMT index score'; para [0052] - 'FIG. 30: EMT changes induced by HGF, OSM and TGFb1 in H292 NSCLC tumor model. Morphological (A), marker (B) and phenotypic (C) changes to cells induced by indicated ligands for 7 days.'; para [0122] 'For clinical application, single patient samples may be analyzed with a control group of samples, taken for example from a clinical trial where the relative indexes correlated with patient response.'), it would have been obvious to one of ordinary skill in the art that such comparison could identify wherein the subject is in a high risk group if the average expression in the subject is higher than the control average expression, and the subject is in the low risk group if the average expression in the subject is lower than the control average expression. Additionally, since Kan teaches patient stratification based on treatment sensitivity or resistance (para [0246]) and a range of treatment options based on clinical factors, it would have been prima facie obvious to the ordinary artisan prior to the effective filing date that treatment selection could be correlated to determined high or low risk based on gene expression, wherein if the subject is in a low risk group, then treating the subject with a treatment that comprises immunotherapy, neoadjuvant therapy and/or chemoradiation; if the subject is in a high risk group, then treating the subject with a treatment that comprises lymph node dissection, adjuvant chemotherapy, adjuvant radiation or post-operative radiation treatment (PORT), chemoradiation, administering an agent that inhibits TGF beta signaling; and/or administering one or more agents targeting malignant cells expressing a p-EMT signature, optionally, further comprising treating the subject with immunotherapy, neoadjuvant therapy and/or chemoradiation.
Kan does not teach assessment of demographic group of the subject and/or control. However, CALIFANO teaches consideration of demographic group of the subject and/or patient (para [0153] 'The Characteristics of the study population largely reflect the demographics of head and neck cancer patients in the United States (Table 2). The HNSCC patients were mainly males (73%, 32 of 44) and Caucasians (91%, 40 of 44), with ages ranging from 45 to 80 years Smoking and alcohol consumption was found in 61% (27 of 44) and 57% (25 of 44) of all patients, respectively. The control population was mainly female (64%, 16 of 25) and Caucasian (56%, 14 of 25), with ages ranging from 18 to 65 Smoking and alcohol consumption was found in 12% (3 of 25) and 36% (9 of 25) of all patients, respectively'). Since CALIFANO teaches a method for diagnosis and prognosis of HNSCC that takes demographic factors into account (para [0146] 'Factors tested for prognostic value included the age, sex, race, smoking status, alcohol use, HPV status, primary tumor site, pathologic tumor stage, pathologic nodal stage, clinical TNM stage, and the presence of promoter methylation of ZNF14, ZNF160 and ZNF420.'), it would have been obvious to one of ordinary skill in the art that consideration of demographic group of the subject and/or control according to Califano could be added to the method of Kan, for improving performance of the method.
Califano teaches the demographic group comprised Males (73%, 32 of 44) and Caucasians (91%, 40 of 44), with ages ranging from 45 to 80 years Smoking and alcohol consumption was found in 61% (27 of 44) and 57% (25 of 44) of all patients, respectively, The control population was mainly female (64%, 16 of 25) and Caucasian (56%, 14 of 25), with ages ranging from 18 to 65 Smoking and alcohol consumption was found in 12% (3 of 25) and 36% (9 of 25) of all patients, respectively). Califano further teaches the demographic group
(para [0146]; para [0153]), and Kan further teaches the control average expression is the median average expression of the one or more p- EMT signature genes or polypeptides for malignant cells obtained from the plurality of tumors for the demographic group; or wherein the control average expression level is an intermediate average expression level of the one or more p-EMT signature genes or polypeptides within the range of average expression for malignant cells obtained from the plurality of tumors for the demographic group (para [0383] - 'Analysis for co-correlation of genes to generate a gene index was performed using custom proprietary software developed by AVEO Pharmaceuticals for co-correlation analysis. Parameter settings for bioinformatics used Pearson correlation with p-values set to 0.01, random gene selection for statistics, either a median centered or non-median centered method, and were auto-anchored. For
calculation of the EMTGS index, negatively correlated genes were flipped for calculating the overall gene index score”). Regarding amended claim 11, the claim simply recites properties of the scores rather than requiring detection or determination of these scores.
Claims 1-4, 9-11, 17, 19, 20, 41, 42, 45-48 are rejected under 35 U.S.C. 103 as being unpatentable over Puram (Puram et al; WO2018/191553) in view of Califano (Califano et al; 20150126374).
Puram teaches a method of treating an epithelial cancer (see abstract) comprising: determining pEMT score comprising a gene selected from SERPINE1, TGF81, MMP10, LAMC2, P4HA2, PDPN, ITGA5, LAMA3, CH13, TNC, MMP2, EMP 3, INHBA, LAMB3, SNAIL2, and VIM (see whole document, claims) and treating the subject based on the expression levels of the genes to calculate a pEMT score. Puram teaches comparing the expression of the subject p-EMT signature genes to a control average expression of the p-EMT signature genes then treating the subject with a treatment selected from lymph node dissection, adjuvant chemotherapy, PORT, neoadjuvant therapy, chemoradiation, or an agent that inhibits TGFB signaling (see whole document, claims).
Puram does not state the subject is in a high risk group if the average expression in the subject is higher than the control average expression, and the subject is in the low risk group if the average expression in the subject is lower than the control average expression. However since Puram teaches comparing gene expression level between tumor and control groups it would have been prima facie obvious to one of ordinary skill in the art that such comparison could identify wherein the subject is in a high risk group if the average expression in the subject is higher than the control average expression, and the subject is in the low risk group if the average expression in the subject is lower than the control average expression.
Puram does not teach assessment of demographic group of the subject and/or control. However, CALIFANO teaches consideration of demographic group of the subject and/or patient (para [0153] 'The Characteristics of the study population largely reflect the demographics of head and neck cancer patients in the United States (Table 2). The HNSCC patients were mainly males (73%, 32 of 44) and Caucasians (91%, 40 of 44), with ages ranging from 45 to 80 years Smoking and alcohol consumption was found in 61% (27 of 44) and 57% (25 of 44) of all patients, respectively. The control population was mainly female (64%, 16 of 25) and Caucasian (56%, 14 of 25), with ages ranging from 18 to 65 Smoking and alcohol consumption was found in 12% (3 of 25) and 36% (9 of 25) of all patients, respectively'). Since CALIFANO teaches a method for diagnosis and prognosis of HNSCC that takes demographic factors into account (para [0146] 'Factors tested for prognostic value included the age, sex, race, smoking status, alcohol use, HPV status, primary tumor site, pathologic tumor stage, pathologic nodal stage, clinical TNM stage, and the presence of promoter methylation of ZNF14, ZNF160 and ZNF420.'), it would have been obvious to one of ordinary skill in the art that consideration of demographic group of the subject and/or control according to Califano could be added to the method of Puram, for improving performance of the method.
Califano teaches the demographic group comprised Males (73%, 32 of 44) and Caucasians (91%, 40 of 44), with ages ranging from 45 to 80 years Smoking and alcohol consumption was found in 61% (27 of 44) and 57% (25 of 44) of all patients, respectively, The control population was mainly female (64%, 16 of 25) and Caucasian (56%, 14 of 25), with ages ranging from 18 to 65 Smoking and alcohol consumption was found in 12% (3 of 25) and 36% (9 of 25) of all patients, respectively). Califano further teaches the demographic group
(para [0146]; para [0153]), and Puram further teaches the control average expression is the median average expression of the one or more p- EMT signature genes or polypeptides for malignant cells obtained from the plurality of tumors for the demographic group; or wherein the control average expression level is an intermediate average expression level of the one or more p-EMT signature genes or polypeptides within the range of average expression for malignant cells obtained from the plurality of tumors for the demographic group (para [0383] - 'Analysis for co-correlation of genes to generate a gene index was performed using custom proprietary software developed by AVEO Pharmaceuticals for co-correlation analysis. Parameter settings for bioinformatics used Pearson correlation with p-values set to 0.01, random gene selection for statistics, either a median centered or non-median centered method, and were auto-anchored. For
calculation of the EMTGS index, negatively correlated genes were flipped for calculating the overall gene index score”). Regarding amended claim 11, the claim simply recites properties of the scores rather than requiring detection or determination of these scores.
Conclusion
No claims are allowed.
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/JEHANNE S SITTON/Primary Examiner, Art Unit 1682
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