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 .
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.
DETAILED ACTION
This action is in response to Applicant’s submission on 9/17/25. Claims 33-48 are pending. Claims 38 and 40-48 are withdrawn pursuant to the Restriction requirement. The election was made without traverse on 10/23/24. Applicant’s election of lower PD-1 in Teff populations and higher CTLA-4 in total T-cell populations as well as the election of the species of prostate cancer remains in effect.
Claims 33-37 and 39 are under examination.
Withdrawn Rejections
The rejection under §112(b) is withdrawn. Applicant has amended the claims to provide antecedent basis for “the cancer”. Note the new rejection under this statute below.
The claim objection is withdrawn in light of the amendment.
The double patenting rejection is withdrawn. The reference patent requires, in every claim, a determination based on comparison to a cancer free subject. The instant claims, as amended, require comparison either to a subject having cancer or (possibly) to the levels in the sample itself. While the reference patent discloses the instantly claimed embodiments, those embodiments are not claimed and not covered by the reference claims. As such, those portions of the reference specification are not deemed to “support” the reference claims and so are not available for a double patenting rejection.
New Rejections Necessitated by Amendment
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 33-37 and 39 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.
Prior to amendment, claim 33 set forth two criteria which must be met to determine a patient was amenable to treatment: the percentage of CD4+ Teff cells expressing PD-1 is lower than in a cancer free subject and the percentage of CD4+ T cells expressing CTLA-4 is higher than in a cancer free subject.
As amended, the claim now sets forth different options for the identification step:
The PD-1 CD4+ Teff is no greater than about 106 cells/µL of a patient amenable to immunomodulatory inhibition of cancer
The total CD4+ T cells are no greater than about 106 cells/µL of a patient amenable to immunomodulatory inhibition of cancer
The PD-1 CD4+ Teff is no higher than about 21% of the CD4+ Teff of a patient amenable to immunomodulatory inhibition of cancer
The PD-1 CD4+ Teff is no higher than about 21% of the total CD4+ T cells a patient amenable to immunomodulatory inhibition of cancer
The total CD4+ T cells is no higher than about 21% of the CD4+ Teff of a patient amenable to immunomodulatory inhibition of cancer
The total CD4+ T cells is no higher than about 21% of the total CD4+ T cells a patient amenable to immunomodulatory inhibition of cancer
CTLA4+ CD4+ T-cells are no less than about 99 cells/µL of the CD4+ T cells of a patient amendable to immunomodulatory inhibition of cancer
CTLA4+ CD4+ T-cells are no less than about 15.6% of the CD4+ T cells of a patient amendable to immunomodulatory inhibition of cancer
First, there are multiple uses of the word “or” in the same list of options. The above is the Examiner’s best interpretation of the possible options set forth; however, there are other interpretations such as only comparing PD+ cell levels to reference PD+ cell levels, rather than, e.g., comparing PD+ cells levels to total CD4+ cell levels. Another interpretation is that the cells per microliter are an absolute in the sample and not compared to another patient.
Second, the claim recites “the sample of a patient amenable to immunomodulatory inhibition of cancer cell growth”. This phrase lacks antecedent basis. The only previous recitation of “a sample” is “a sample from the patient” where “the patient” refers to “a patient with a cancer”. Since the “a patient amenable to immunomodulatory inhibition of cancer cell growth” necessarily has cancer—else they would not be amenable to inhibition of cancer cell growth—it appears on its face that these are the same individual. However, that is not a reasonable interpretation since it would make the later comparison steps meaningless, comparing a sample to itself. Lacking any reasonable recitation of “a sample of a patient amenable to immunomodulatory inhibition of cancer cell growth”, the phrase “the sample of a patient amenable to immunomodulatory inhibition of cancer cell growth” is indefinite.
Third, claim 33 now uses the term “about”. The term itself is not per se indefinite. For example, claim 39 previously (and still) recites the term “about” and this term is not considered indefinite in this claim. Claim 33 previously set forth two requirements that must be determined in order to conclude a subject is amenable to treatment. Thus, the use of “about” in claim 39 was not indefinite as this “about” was/is used in the context of describing levels in the sample independent of the determining/identifying step, i.e., a property of the sample which reasonably warns other of the limits of infringement.
However, claim 33 uses the term “about” for the identification step which is critical to defining the scope of infringement. Moreover, there is no guidance nor any examples in the specification as filed as to the metes and bounds of “about”. There is only a 7 cell/µL difference between the “cannot be greater than” and “cannot be less than” stipulations of the claim. If the levels of cells in the sample are at 107 cells/µL, this is reasonably “about” 106; however, it is unclear if that amount would be considered “no greater” than about 106 or if the value is in fact greater than 106. If 107 is not greater than “about 106”, then it is entirely unclear from the specification as filed what amount would be excluded from this evaluation. Further, it would also be reasonable to interpret a 10% variation of a given value, meaning that 107 cells is “less than about 99 cells” because it would be reasonable to interpret this as extending to “no less than 108 (109) cells” (about 99 cells given a +/- 10% variation of 9 or 10 cells). While close prior art is a consideration for the indefiniteness of “about”, it is not the sole determining factor. In this case, the values themselves are so close together that a single value may result in identifying a patient for treatment as well as not for treatment.
Moreover, it is unclear whether only a single option is required to be met or if the list is setting forth the various requirements for the claimed conclusion. Take for example a patient sample where the PD-1+ CD4+ Teff cells are no higher than 21% of the total CD4+ T cells of the reference patient but higher than 21% of the CD4+ T cells of the reference patient. This meets one criterion for identification but not another. It is unclear if meeting any of the criteria is sufficient for identification or if the list is all of the alternatives a sample must meet for identification. In other words, it is unclear if the list is establishing a list of alternatives or establishing a list of requirements.
Moreover, step (b) recites “using” flow cytometry. Since this step does not set forth any steps involved in that “use”, it is unclear what method/process applicant is intending to encompass. A claim is indefinite where it merely recites a use without any active, positive steps delimiting how this use is actually practiced; see MPEP §2173.05(q).
Finally, when comparing sample levels to a “sample of a patient amenable to immunomodulatory inhibition of cancer cell growth”, one could arrive at different conclusions regarding the same sample. The method is one of determining if a patient may be treated with an anti-CTLA4 antibody; however, there is no requirement that the comparison patient is amenable to any particular immunomodulation. This may be amenable to CTLA-4 immunotherapy or some other immunotherapy. As these levels are disclosed as indicative of immunomodulatory therapy efficacy, the therapy itself that the patient is amenable to will affect the levels of these cells.
MPEP § 2173.02 (II) states that one of the purposes of examination under 35 USC § 112, second paragraph is to determine whether the claim apprises one of ordinary skill in the art of its scope and, therefore, serves the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent. See, e.g., Solomon v. Kimberly-Clark Corp., 216 F.3d 1372, 1379, 55 USPQ2d 1279, 1283 (Fed. Cir. 2000). See also In re Larsen, No. 01-1092 (Fed. Cir. May 9, 2001) (unpublished). If the language of the claim is such that a person of ordinary skill in the art could not interpret the metes and bounds of the claim so as to understand how to avoid infringement, a rejection of the claim under 35 U.S.C. 112, second paragraph, would be appropriate. See Morton Int’l, Inc. v. Cardinal Chem. Co., 5 F.3d 1464, 1470, 28 USPQ2d 1190, 1195 (Fed. Cir. 1993). In this case, the amendments introduce multiple potential options, several uses of the word “or”, evaluation based on “about” and changes a “cancer free subject” to a subject that has cancer and is amendable to some unclaimed immunotherapy.
Therefore, claims 33-37 and 39 are indefinite.
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 33-37 and 39 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (natural phenomenon) without significantly more.
Step 1: It must first be determined if the claim is to a statutory category and, if so, proceed to step 2A prong 1. The claims are a method and fall within the statutory category of a process.
Step 2A, prong 1: Prong 1 requires the Examiner to evaluate whether the claim recites a judicial exception and, if so, proceed to prong 2. In this case, the claims recite identifying a patient with cancer “for treatment with an anti-CTLA4 antibody product” if certain levels of cells are observed in the sample of that patient.
In other words, the claims recite observing the natural expression of CTLA-4 and PD-1 in natural CD4 cells (isolated from subjects) and informing others of the natural correlation of this information (“identifying”) to the amenability of the subject to treatment, which falls under the judicial exception of observing a natural phenomenon.
Step 2A, prong 2: Prong 2 requires the Examiner to evaluate whether the claim recites additional elements that integrate the exception into a practical application of that exception and, if not, proceed to step 2B. In order to integrate the recited judicial exception into a practical application, the claim will apply, rely on, or use the judicial exception that imposes a meaningful limit such that the claim is more than a drafting effort to monopolize the judicial exception. Examiners evaluate integration by identifying additional elements in the claim beyond the judicial exception and evaluating those elements individually and in combination to determine whether they integrate the exception in to a practical application. Examples that have been found by the Courts in which the exception was not integrated into a practical application include:
Mere instructions to implement an abstract idea on a computer
Adding generic instructions that the judicial exception should be used ("apply it")
Adding insignificant extrasolution activity to the exception ("mere data gathering")
Generally linking the use of the exception to a particular technological environment or field of use
In this case, the “identifying” step recites the judicial exception itself, i.e., describes the basis for others to make the relevant conclusion/identification. Even if the “identifying” is considered an application of the observation, this is recited at such a high level of generality (“identifying” with no further limitations) and is merely a mental conclusion that it falls under generic instructions to use the judicial exception somehow; further note that the determining step is conditional and not always practiced (“if”) while the actual values (lower; higher) are not a step taken by the practitioner but a description of the natural expression of the biomarker, i.e., the natural phenomenon that has been observed. The remaining steps a-b are directed to the necessary data gathering steps and so fall under the category of insignificant extrasolution activity.
Step 2B: Where a claim does not integrate the exception, a claim may nevertheless be patent eligible, for example where additional elements are “significantly more” than the exception such that the additional elements were unconventional in combination. Considerations include whether or not the claim adds a specific limitation or combination of limitations that are not well-understood, routine, conventional activity in the field, which is indicative that an inventive concept may be present; or simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, which is indicative that an inventive concept may not be present. In this case, isolating, quantifying, and comparing are all basic tools of diagnostic science and are routine and conventional even in this particular combination. See for example US 6187534 claim 11 (previously cited), US20070026465 claim 1 (previously cited), and US20130177925 claim 14 (previously cited).
Using flow cytometry to quantify cells and antigens such as T cells is also well-known and conventional. See:
US20130017550 (form 892) claims 1, 2, 11, 14
US20120276004 (form 892) claims 1, 7, 9, 12
US20070237790 (form 892) claims 28, 29, 30
US20070218032 (form 892) claims 1, 2, 5, 8
Yates (form 892) using flow cytometry to analyze CTLA-4 on CD4+ T cells
The particular biomarkers being quantified and compared and the particular samples being isolated are all part of the judicial exception itself, so the step 2B analysis turns on the methods by which this data is gathered. Isolating a sample from a subject to be diagnosed, quantifying the relevant biomarker, and comparing that biomarker to a control all represent routine steps in the diagnostic field.
The fact pattern is similar to that in Mayo v Prometheus case. In Mayo, a drug was administered, the natural metabolites were measured, and a conclusion was made about treatment efficacy; this was deemed ineligible by the Supreme Court. In Mayo, a level of the metabolite "less than about 230 pmol per 8x108 red blood cells [indicated] a need to increase the amount of said drug”. Such claim limitations were found to be a description of the correlation itself and not “significantly more”. It was also found that steps prior to this constituted routine data gathering, instructing the artisan to engage in conventional, well-known practices and then "warning" the user of the implications of the data. The same is true here, where there is no drug administered but the natural expression of these cells is being measured and describe the expression patterns (percentage) correlated to the conclusion. This was not eligible in Mayo and thus the instant claim(s) are not patent eligible.
Finally, it is noted that whether or not it was routine and conventional to look at these biomarkers in these cells at these levels is not germane to the analysis as this is just a description of the judicial exception and where to observe the judicial exception. The Court in Ameritox v Millennium 88 F.Supp.3d 885 (2015) determined that while the decision in Mayo tied the notion of well-understood and conventional steps to "activity already engaged in by the scientific community", the Court when deciding Myriad v Ambry couched the question as "techniques that a scientist would have thought" to use. This conclusion is supported not only by the Ameritox case, but also by the decision in Ariosa v Sequenom, where the sample was clearly unconventional (maternal plasma had routinely been disregarded as medical waste) but when provided with information regarding the natural relationship between cffDNA in maternal plasma and a diagnosis, the remaining portion of the claim was drawn to no more than "known laboratory techniques". This is also supported by the decision in Myriad v Ambry, where the probes for BRCA1 were previously unknown, but represented no more than a standard technique for detection; "any scientist engaged in obtaining the sequence of a gene in a patient sample would rely on these techniques".
Thus, claim 33 is directed to a judicial exception without significantly more.
Regarding claims 34-36, the claims are directed solely to the “anti-CTLA-4 antibody product” that is the focus of the potential treatment. No treatment is ever provided in the claims and the claim as a whole is describing the judicial exception itself, e.g., which product “for treatment” is identified for the subject given observation of certain expression percentages/levels. Thus, under both 2A prong 2 and 2B, there are no additional elements.
Regarding claim 37, in the same way as claims 34-36, this claim is directed to the preamble of claim 33 and the judicial exception, i.e., which cancer the patient has for treatment. This does not dictate a practical application (no treatment is provided) and generally describes where the observation is to be made, which is part of the data gathering and/or environment.
Regarding claim 39, this claim is solely directed to the percentages observed in the cells, i.e., describes the natural phenomenon/correlation itself. The claim does not provide any additional limitations beyond the judicial exception and so cannot provide significantly more than the judicial exception.
Therefore, claims 33-37 and 39 are not patent eligible.
Response to Arguments
Applicant's arguments filed 9/17/25 have been fully considered but they are not persuasive.
Applicant argues that the step of “identifying” is an active step and so there is no judicial exception. This is not persuasive. Whether or not identifying is an active step is not informative of whether or not the claims recite a judicial exception. The claims clearly still recite a judicial exception, i.e., making the claimed identification based on observed levels of a biomarker.
Applicant argues that the claims integrate the judicial exception because the identifying step is based on specific numbers. This is not persuasive. The use of “specific numbers” is a description of the judicial exception itself and is not “in addition” to the judicial exception. This fact pattern is similar to that in Mayo v Prometheus case. In Mayo, a level of the metabolite "less than about 230 pmol per 8x108 red blood cells [indicated] a need to increase the amount of said drug”. Even though this conclusion—this “identification”—was made using specific numbers, such claim limitations were found to be a description of the correlation itself and not “significantly more”. It was also found that steps prior to this constituted routine data gathering, instructing the artisan to engage in conventional, well-known practices and then "warning" the user of the implications of the data; this was not eligible in Mayo and thus the instant claim(s) are not patent eligible. Further, it is not found persuasive that “identifying” is an active step. This step is practiced upon the observation of the gathered data similar to the “indicated” in Mayo. Additionally, as previously set forth in the rejection, this identification may not even happen (“if”) and so the claim covers the absence of this identification. Thus, solely observing the levels and not making the identification is within the scope of the claim.
Applicant argues the method improves current cancer treatment. As noted previously, there is no claimed treatment step and so there is no claimed limitation that any patient is ever treated. Thus, the claim is not integrated into a cancer treatment. Even if arguendo the claim could be considered an improvement to cancer treatment, this argument is not commensurate in scope with what is now claimed.
Applicant argues identification is a practical application. As set forth in the rejection, this identification step is part of the judicial exception and so is not an “additional element”.
In the 2016 eligibility guidance, the Office set forth examples involving “Julitis”. Claim 2 recited the steps of obtaining a sample, detecting the biomarker, and diagnosing the patient. This was deemed ineligible. Applicant’s argument that “identifying” is sufficient is not persuasive for the same reasons that “diagnosing” did not make that example claim eligible. The Office provided additional guidance in 2019 regarding an example of treating kidney disease. Here, a ratio was calculated “to identify” a particular patient. This claim also included a treatment step. This claim is cited as ineligible. That example claim also includes evaluating biomarkers to “identify” a patient. Even including a generic treatment step—which the instant claims lack—was insufficient to be considered a practical integration and so a claim lacking any additional steps after the identification similarly lacks such integration, i.e., “identification” is part of the judicial exception and/or not a practical application itself.
Applicant argues the specific numbers are sufficient to avoid the “high generality” conclusion. However, as stated above, these numbers represent the judicial exception, e.g., what the identification is “based on”.
Applicant argues the specific biomarkers are not part of the judicial exception. This is not persuasive because it is the natural relationship between these specific biomarkers at these specific levels and the ultimate conclusion, i.e., the judicial exception. The step of quantifying them is part of the necessary data gathering and is addressed above.
Applicant argues that flow cytometry is unconventional because “there is no reason why one skilled in the art would generally use flow cytometry to measure these specific biomarkers in specific cell types. As above, this in not the legal standard. The Court in Ameritox v Millennium 88 F.Supp.3d 885 (2015) determined that while the decision in Mayo tied the notion of well-understood and conventional steps to "activity already engaged in by the scientific community", the Court when deciding Myriad v Ambry couched the question as "techniques that a scientist would have thought" to use. Thus, the relevant question when determining whether or not a technique was routine and conventional is not necessarily that the steps were strictly practiced in the art prior to the invention as in Mayo, but whether the techniques are those that would have been thought of by the artisan given the relevant information. This conclusion is supported not only by the Ameritox case, but also by the decision in Ariosa v Sequenom, where the sample was clearly unconventional (maternal plasma had routinely been disregarded as medical waste) but when provided with information regarding the natural relationship between cffDNA in maternal plasma and a diagnosis, the remaining portion of the claim was drawn to no more than "known laboratory techniques". This is also supported by the decision in Myriad v Ambry, where the probes for BRCA1 were previously unknown, but represented no more than a standard technique for detection; "any scientist engaged in obtaining the sequence of a gene in a patient sample would rely on these techniques".
Thus, the relevant question is “once provided a reason to quantify the percentages of CD4+ T cells expressing CTLA-4 and the percentages of CD4+ Teff- cells expressing PD-1 in the sample, what methods would the skilled artisan have thought of?”.
Applicant provides no objective evidence as to why there is “no reason” a skilled artisan would have used flow cytometry to quantify these cells. Applicant is reminded that “arguments of counsel cannot take the place of factually supported objective evidence" (MPEP§2415). Rather, flow cytometry is a conventional, widely-used method for measuring such biomarkers. There is no unconventional aspect of the flow cytometry itself. The rejection cites several pieces of prior art demonstrating that flow cytometry has been actually used to quantify T cells, including the analysis of CTLA-4. Thus, there is no apparent reason why one of skill in the art would have no reason to use flow cytometry in the quantification step when this same technique has been actually used to do so prior to the instant effective filing date. There is no evidence that the “specific subtype” renders flow cytometry an unconventional choice.
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 ADAM M WEIDNER whose telephone number is (571)272-3045. The examiner can normally be reached M-T 9-18; W-R 9-15.
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/Adam Weidner/ Primary Examiner, Art Unit 1675