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 .
Response to Arguments
Applicant’s arguments, see pages 8-10, filed 9/22/25, with respect to 112a rejection and 103 rejection over Hanahan (WO201915884) have been fully considered and are persuasive. The rejections of claims 21, 22, and 25 has been withdrawn because of the cancellation of claim 22, the amendment to claim 21 to recite cancer sample and remove “miRNA” from claim 25, and the declaration of Hanahan (discussed below).
The Declaration of Douglas Hanahan under 37 CFR 1.130 filed 9/22/25 is sufficient to overcome the rejection of claims 21 and 25 based upon WO 201915884. Hanahan states that the other inventors on the ‘884 publication did not contribute to the conception or reduction to practice of the invention claimed in the instant application, nor did they make an inventive contribution to any portion of the ‘884 publication that could be relied upon to establish the patentability of the claims of the instant application. The ‘884 publication is not prior under the 102(b)(2)(A) exception.
Claim Rejections - 35 USC § 101
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 21 and 25 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a law of nature and/or natural phenomenon and an abstract idea without significantly more. The claims are directed to a process (method of identifying an agent), which is one of the four categories of statutory subject matter. The claims recite a method of identifying an agent that modulates the expression and/or activity of FMRP protein, an mRNA encoding FMRP and/or an FMR1 gene and inhibits the cancer or cancer metastasis intrinsically resistant to or has assigned adaptive resistance to immunotherapy comprising providing 1) a cancer sample expressing FMRP; 2) contacting the sample with a test agent; 3) measuring the level of expression or activity in the sample; 4) comparing the level of expression or activity to a control sample not contacted with the test agent; and 5) selecting the agent that decreases the level of expression and/or activity of FMRP relative to a control sample and inhibits the cancer or cancer metastasis intrinsically resistant to or has assigned adaptive resistance to immunotherapy. The limitation ‘and inhibits the cancer or cancer metastasis intrinsically resistant to or has assigned adaptive resistance to immunotherapy’ recited in the pre-amble and the last two lines of amended claim 21 are directed to a functional limitation of the product because there are no method steps to carry out or observe this limitation. If the product decreased the level of expression and/or activity of FMRP than it would inherently have the functional limitation.
Prong one of Step 2A:
Steps 3) and 4) recites determining the expression level or activity of FMRP in a cancer sample having the test agent and comparing the expression level or activity of FMRP in control sample having the test agent which is a judicial exception. See MPEP 2106.04(b). The method steps and test agent are recited at a high level of generality. The steps read on basic tools of scientific and technological work and are not patentable. Administering a test compound to a cancer sample expressing FMRP, determining the expression level and/or activity of FMRP and comparing the results to an expression level of activity of FMRP in a control sample is comparable to a correlation that is the consequence of how a certain compound is metabolized by the body, Mayo Collaborative Servs. v. Prometheus Labs., 566 U.S. 66, 75-77, 101 USPQ2d 1961, 1967-68 (2012) in to which the courts have identified as examples of laws of nature or natural phenomenon. See MPEP 2106.04(b)(I). Furthermore, the BRI of determining and comparing an expression level or activity requires performing an arithmetic calculation in order to obtain the expression level and comparing it to a control step. The method steps therefore recite a mathematical calculation. This limitation falls into “mathematical concept” grouping of abstract ideas Steps 3) and 4) fall into “mental process’ groupings of abstract ideas. In addition, the limitations in steps 3) and 4) describe a natural correlation relationship between the expression level and/or activity of FMRP and a test agent.
The limitation ‘selecting the test agent that decreases the level of expression and/or activity of FMRP relative to a control sample’ in Step 5) is an abstract idea because it is directed to a mental step. Furthermore, the limitation in step 5) is a mental step of selecting an agent combined with an intended use or functional limitation of the agent and there is no administration step to integrate the mental step into a practical application. There are no method steps for the using the agent and in order to qualify as a “treatment” or “prophylaxis” limitation for purposes of this consideration, the claim limitation does not affirmatively recite an action that effects a particular treatment for a cancer or cancer metastasis intrinsically resistant to or has acquired resistant to immunotherapy. The limitation does not actually provide a treatment, e.g., it is merely an intended use of the claimed invention or a field of use limitation, then it cannot integrate a judicial exception under the “treatment or prophylaxis’ consideration. See MPEP 2106.04(d)(2) a. The particularity or generality of the treatment or prophylaxis.
The claim as a whole is directed to a judicial exception and thus requires further analysis under step 2B to determine if the claim as a whole amount to significantly more than the exception itself.
Prong two of step 2A:
Besides the abstract idea in steps 3), 4) and 5) and law of nature or natural phenomenon in step 3), the claims recite additional elements of providing a cancer sample in step 1) and contacting the sample with a test agent in step 2). Although the limitation indicates that the sample is contacted with a test agent, it does not provide any information about the agent or method steps for determining the expression level or activity of FMRP, but instead covers any possible test agent, including products not man made. In fact, these steps are recited at such a high level of generality that steps 3)-4) are drawn to insignificant extra-solution activity or steps of mere data gathering. See MPEP 2106.05(g). Accordingly, step 1), 2), and 3) does not integrate the recite judicial exception into a practical application and the claim is therefore directed to the judicial exception.
Step 2B:
This part of the eligibility analysis evaluates whether the claim as a whole amounts to significantly more than the recited exception, MPEP 2106.05. As explained with respect to Prong Two of step 2A, the claimed method reads on any method of determining level of expression or activity of FMRP and any agent. The steps 1)-4) recited in instant claim 21 are directed to an assay at a high level of generality that would read on well-understood, routine, conventional activity (WURCA). The courts have recognized determining the level of a biomarker in sample by any means is as laboratory technique that is WURCA in the life science arts when they are claimed in merely a generic manner. See MPEP 2106.05(d).
Instant claim 25 is directed to a ‘wherein’ clause for the agent. There are no additional methods steps or structural limitations of the agent other than it reducing FMNRP expression or activity to amount to more than the judicial exception.
Thus, claims 21 and 25 are not patent eligible.
Response to Arguments
Applicant's arguments filed 9/22/25 have been fully considered but they are not persuasive.
In response to applicant’s argument that the claims involve a concrete, laboratory-based process, the argument is not found persuasive because while step 2 and 3 provide physical manipulations of tangible and materials (using physical or chemical interactions) and not merely observing a natural phenomenon or performing mental steps, the argument is not found persuasive because the active steps are recited a high level of generality and are data gathering steps. See MPEP 2106.05(g). A skilled artisan would have to continue to step 2B to determine if there is something significantly more to the claim.
Applicant’s argument that these steps transform the sample by introducing a test agent and measuring a specific biological outcome, akin to the transformation process found eligible in Diamond v. Diehr 450 US 175 (1981), where a process step was deemed patent-eligible, the argument is not found persuasive because Diamond v. Diehr was directed to a process of curing synthetic rubber. Each case is decided on it’s own merits. As stated above, the active steps are data gathering steps recited at high level of generality.
In response to applicant’s arguments that the claim’s purpose is specific, practical application in the field of oncology, addressing real-world problem and does not merely observe a natural correlation but uses it to identify novel therapeutics agents, providing a “specific technological improvement” in cancer therapy (see Under the 2019 Revised Patent Subject Matter Eligibility Guidance (2019 PEG), the arguments are not found persuasive because the claims are directed to a law of nature and data gathering step and has to be further examined under step 2B to determine if there is something significantly more to the claim.
In response to applicant’s argument that the requirement that the selected agents “inhibits the cancer or cancer metastasis’” ties the method to measurable, therapeutic outcomes, distinguishing it from claims that merely diagnose or observe, as in Mayo, the argument is not found persuasive because the claimed method is directed to a law of nature and data gathering step and has to be further examined under step 2B to determine if there is something significantly more to the claim.
In response to applicant’s argument that the claim is limited to identifying an agents modulates FMRP and inhibit cancer with specific characteristics and this specificity avoids preempting all uses of the natural relationships between FMRP and cancer, unlike the broad diagnostic claims in Mayo, the argument is not found persuasive because to the claimed method is directed to a law of nature and data gathering step and has to be further examined under step 2B to determine if there is something significantly more to the claim.
In response to applicant’s argument that claim’s focus on immunotherapy-resistant cancers and similar to Vana Pharms. Inc. v. West-Ward Pharm, Int’l Ltd, where a treatment method applying a natural relationship was deemed eligible, the argument is not found persuasive because there is treatment method recited in the instant claims. As stated above, the claimed method is directed to a law of nature and data gathering step. The claim has to be further examined under step 2B to determine if there is something significantly more to the claim.
Applicant’s argue that the integration of mental steps into a physical process aligns with Classen Immunotherapeutics, Inc. v. Biogen IDEC, where a method involving physical steps and evaluation was found eligible. The argument is not found persuasive because there are no active steps encompassing a treating cancer. The active steps are merely recited in a generic manner as set forth in MPEP 2106.05(d)(II), where the courts considered the case to be recognized as well-understood routine, conventional activity in the life science. In addition, the claimed method is directed to a law of nature and data gathering step and has to be further examined under step 2B to determine if there is something significantly more to the claim.
Applicant further provides the following arguments regarding step 2B:
Unconventional Combination of Steps: The claim combines specific steps (providing an FMRP-expressing sample, contacting it with a test agent, measuring FMRP levels, comparing to a control, and selecting agents that inhibit resistant cancers) that are not routine or conventional in the field of cancer drug discovery. While individual techniques like measuring protein expression may be known, the specific combination targeting FMRP modulation in the context of immunotherapy-resistant cancers is novel and non-obvious. The focus on FMRP in the novel context of immunotherapy-resistant cancers, adds an inventive element not well-understood, routine, or conventional in oncology, distinguishing the claim from the routine data collection in Mayo.
Applicant’s arguments are not found persuasive because under step 2B, it is determined if the claims adds significantly more to the claim and does not rely on the judicial exception itself to provide the inventive concept of the claim that renders it eligible. See MPEP 2106.05. The contacting a cancer sample with an agent and measuring FMRP expression or activity and comparing the results to a control sample are recited a high level of generality. See MPEP 2106.04(d)I and 2106.05II. In addition, the claim does not recite a treatment step. Step 5 is a mental step of selecting a test agent that has a certain activity and the test agent has functional limitations recited in the step.
Specific Biological Context: The claim’s application to cancers with intrinsic or adaptive resistance to immunotherapy addresses a specific, unmet clinical need. This targeted approach goes beyond generic drug screening methods and provides a solution to a particular problem, akin to the inventive concept in Rapid Litigation Mgmt. Ltd. v. CellzDirect, Inc., 827 F.3d 1042 (Fed. Cir. 2016), where a novel method of preserving hepatocytes was deemed eligible for improving an existing technological process.
Applicant’s arguments are not found persuasive because with respect to detecting the FMRP in the sample having the test agent compared to a control, this is necessary data gathering, and is directly informed by the natural correlation. The actual steps (gathering a sample and performing) are routine and conventional in the art and recited at a high general level. See also MPEP 2106.05(d), which provides guidance in the analysis of what is considered well-known routine and conventional in the art. In this instance, the claim merely provides for routine processes of obtaining a sample and generally performing any data gathering step in life sciences for a gene identified by the judicial exception correlation (similar to the Mayo decision referenced in the MPEP).
With respect to applicant comparing the claimed method to claims in Rapid Litigation Mgmt. Ltd v. CellzDirect, the argument is not found persuasive because the claims merely add generic method steps to perform the method.
3. Tangible Outcome: The selection of agents that both decrease FMRP expression/activity and inhibit cancer growth or metastasis results in a tangible outcome: identifying potential therapeutics. This is not a mere observation of a natural phenomenon but a method that produces a practical result, further supporting an inventive concept.
Applicant’s arguments are not found persuasive because the selection of agents is a mental step based on data in the data gathering steps that were well-understood, routine, conventional activity. See MPEP2106.05(d)(II). The data gathering steps were recited at high level of generality. The limitation ‘decreased the level of expression or activity of FMRP relative to a control sample and inhibits the cancer or cancer metastasis intrinsically to or has acquired resistance to immunotherapy’ in step 5 is not directed to a method of treating but a functional limitation of the test agent.
Thus, the 101 rejections remains for the reasons of record.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 21 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Bagni (US 20130149297, of record) taken with Joshua Alumkal (US 20110195432).
Bagni teaches a method of inhibiting an FMR1 gene, at the FMR1 mRNA and FMPP protein level, using an FMR1 inhibitor (pages 1 and 21, see also claims 8-10 ). Bagni teaches that a sample that is FMRP positive needs to be provided for expression analysis or determining the level of an FMR1 gene product (paragraphs 19 and 58). Bagni teaches that an FMR1 gene inhibitor such as siRNA needs to be in contact with a tumor site by means of injecting the siRNA into tumors to affect the expression of FMRP (paragraph 104]) and an inhibitory agent or siRNA, can also be used with the sample for in vitro testing (FIG. 7, paragraph 31). Bagni teaches that the FMRP expression and effect of FMR1 silencing (i.e. activity) are determined in tumor and normal tissues (FIG. 9 paragraph 35). In this regard, Bagni also teaches that the levels of FMR mRNA and protein and their in vitro effects in cancer growth (i.e. activity) were determined when samples of tumor cell lines were treated with inhibitor such as FMR1 siRNA or control siRNA (i.e. untreated control)(paragraphs 30-32). Bagni further teaches that method of preventing metastasis comprising inhibition of functional expression of the FMR1 gene by administering an FMR1 inhibitor (i.e. by an inhibitory agent) (paragraph 68) and the inhibition of functional expression can be achieved at the DNA level/FMR1 gene level, mRNA and FMRP protein level (paragraph 69).
Bagni et al. do not specifically teach a method for screening for the inhibitor comprising contacting a cancer sample expressing FMRP, determining the level of expression or activity of FMRP in the sample compared to a control sample not contacted with the test agent, and selecting an agent that decreases the level of expression or activity of FMRP.
The limitation ‘selecting the test agent that decreases the level of expression and/or activity of FMRP and inhibits the cancer or cancer metastasis intrinsically resistant to or has assigned adaptive resistance to immunotherapy’ recited in amended claim 21 is directed to a mental step combined with a functional limitation or intended use of the test agent because there are no method steps to carry out or observe this limitation. If a test agent decreased the level of expression and/or activity of FMRP than it would inherently have the limitation in instant claim 21.
However, Alumkal teaches methods for selecting agents for treating cancer comprising contacting a sample with an inhibitor, measuring the expression level or activity of a HDAC6 deacetylase in the sample, comparing the expression level or activity in the sample to a control and identifying an agent that reduced the expression or activity of HDAC6. For example, see 1-2, 7-10, 13-16, and 22-23.
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the teaching of Bagni taken with Alumkal to use the claimed method to determine if an inhibitory agent possess the desired property before using the inhibitor in a method for treating cancer, namely to arrive at the claimed invention. See MPEP 2143(I)Examples of Rationales (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art. One of ordinary skill in the art would have been motivated to combine the teaching to use the claimed method to identify agents that successfully reduce expression or activity of FMRP in a sample compared to a control before using the agents in future research or therapeutic studies. Instant claim 25 is directed to a ‘wherein’ clause for the agent. There are no additional methods steps or structural limitations of the agent in claim 25 other than it reducing FMRP expression or activity. If the agent decreases the level of expression or activity of FMRP, then it would read on the functional limitation in instant claim 25 because when the agent reduces the expression level of activity of FMRP it would result in the agent inhibiting or impairing the binding of the FMRP to a target mRNA.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Response to Arguments
Applicant's arguments filed 9/22/25 have been fully considered but they are not persuasive.
In response to applicant’s arguments that the pre-amble gives patentable weight to the claimed because the preamble gives, meaning, and vitality to the claims (see MPEP 2111.02) and the claims are not merely directed to mental steps, rather the claims recite a practical application through a specific transformation method for identifying agents for immunotherapy-resistant cancer, the arguments are not found persuasive because there are no active steps of delivering the agent to a subject or using the agent to treat a subject having cancer or cancer metastasis intrinsically resistant to or has acquired adaptive resistance to immunotherapy. Steps (1) and (2) are the only active steps required to be made obvious by the prior art because steps (3)-(5) are mental steps.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). This is the case here since the rejection is under 103 and while it is acknowledged that Alumkal (US ‘432) is directed to HDAC inhibitors and not FMRP, the method steps for identifying an inhibitor of a target sequence are made obvious by ‘432. The ’432 is considered analogous prior art and does not teach away from using a method of identify an agent that inhibits a target sequence in a cancer cell. See MPEP 2143(I)Examples of Rationales (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art. One of ordinary skill in the art would have been motivated to combine the teaching to use the claimed method to identify agents that successfully reduce expression or activity of FMRP in a sample compared to a control before using the agents in future research or therapeutic studies.
Conclusion
See attached PTO-326 for disposition of claims.
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.
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/BRIAN WHITEMAN/ Primary Examiner, Art Unit 1636