DETAILED ACTION
Applicant is notified that the examiner for this action has changed.
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 Applicant Reply
This Office Action is in response to Applicant’s reply of 2 December 2025. Applicant’s remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance.
Note: The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
This action is made NON-FINAL.
Election/Restrictions
Applicant's election with traverse of MDM2 in the reply filed on 7 May 2025 was not previously addressed and is herein acknowledged. The traversal is on the ground(s) that the claims that list genes include language such as “one or more genes selected from”, “at least one”, and “each of the … genes” and that the application describes that genetic analysis of multiple genes can be performed using current technologies (such as in [0089]), so restriction to a method of analyzing only one gene or one specific group of genes would be improper. Per MPEP §808.01(a): “A requirement for restriction is permissible if there is a patentable difference between the species as claimed and there would be a serious search and/or examination burden on the examiner if restriction is not required”. Both the requirement of a patentable different and a serious search burden were met in the Requirement for Restriction mailed 7 March 2025. The Requirement stated that the gene targets for which election was required are at different gene regions and have varying biological effects, so the inventions directed to the species of the method wherein different genes are selected are patentably distinct. A serious search burden was also stated in the Requirement, since a reference pertaining to the method using a specific selection of genes would not pertain to a different species of the method that uses a different selection of genes (for example, a species of the method wherein MDM2 is selected would require searches that include MDM2, which would not be expected to yield references useful for the examination of a species of the method wherein CDK6 and CCNE1 are selected). Applicant neither argues for why there is not a patentable difference between species or why there would not be a significant search or examination burden if restriction were not required, as the showing that multiple genes could be analyzed by current technologies does not show that there is no additional burden in searching for methods utilizing a different gene or set of genes.
Furthermore, regarding Applicant’s statement that the traversal of the election requirement is “to the extent that the Office intends to restrict applicant and/or examine only embodiments that involve analyzing a single gene”, Examiner notes that the list of genes provided in the Requirement for Restriction were conjoined by the operator ‘or’, which, when not stated as being exclusive, includes all possible combinations of the list. Claims at the time of the Requirement being mailed were directed to methods wherein combinations with multiple genes were explicitly encompassed by the claim (e.g., claim 4 having “one or more genes” of the list provided in the claim). Applicant was therefore given the option of electing a single species of the method that analyzed any one gene or any combination of the listed genes and was not limited to only embodiments that involve analyzing a single gene.
The requirement is still deemed proper and is therefore made FINAL.
As the search for the species of the method utilizing MDM2 also uncovered references pertaining to species of the method utilizing JAK1 and/or JAK2, the application has been examined for species of the method utilizing MDM2, JAK1, JAK2, or JAK1 and JAK2. Claims 3 and 11 are rejoined, insofar as they are directed to examined species, because species of the method utilizing JAK1, JAK2, or JAK1 and JAK2 have been examined in addition to the elected species of the method utilizing MDM2.
Newly amended claims 12 and 15 are directed to species that are independent or distinct from the elected species for the following reasons. All species encompassed by claim 12 require analysis of at least one gene from the list of CDKN2A through JAK3 given on lines 4-5 of claim 12 and analysis of at least one gene from the list of CCND1 through MYC, so it does not encompass the elected species of method using only MDM2 or the further examined species of method using one or both of JAK1 and JAK2. Similarly, claim 15 encompasses a single species that requires analysis of each gene listed on lines 4-5 and each gene listed on lines 8-9, which is different from the elected species and further examined species. Therefore, claims 12 and 15 are not drawn to the elected species or further examined species. Accordingly, claims 12 and 15 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b).
Claim Status
Claims 1-19 are pending.
Claims 10, 12, and 15 are amended.
Claims 12 and 14-15 are withdrawn, see Election/Restriction section above.
Claims 3 and 11 have been rejoined insofar as they are directed to further examined species, see Election/Restriction section above.
Claims 1-11, 13, and 16-19 are under examination.
Withdrawn Objections/Rejections
The objections to the specification in the Office Action mailed 11 June 2025 have been withdrawn in view of the amendment to the specification filed 2 December 2025. However, new objections to the specification are made in this Office Action.
The rejection of claim 10 and claims 11-16 and 18-19 depending upon claim 10 under 35 U.S.C. 112(d) due to claim 10 depending upon itself has been withdrawn in view of the amendment to the claim correcting its dependency.
Any and all rejections of claims 12 and 14-15 are withdrawn in view of the claims being withdrawn and not under examination, see Election/Restriction section above regarding the withdrawal of claims 12 and 14-15.
The rejection of claims 1-2, 4-10, 12-13, and 15-19 under 35 U.S.C. 101 has been withdrawn in part and replaced with a modified rejection of claims 1-11, 13, and 16-19 under 35 U.S.C. 101. This withdrawal is further discussed below the modified 35 U.S.C. 101 rejection in this Office Action.
The rejections of claims 1-2, 5-10, and 17-19 under 35 U.S.C. 103 over Galon in view of Spetzler, as well as of claims 4, 12-13, and 15-16 under 35 U.S.C. 103 over Galon in view of Spetzler and further in view of Singavi, have been withdrawn and replaced with new rejections of claims 1-3, 5-11, 17-19 under 35 U.S.C. 102 over Ribas and claims 4, 13, and 16 under 35 U.S.C. 103 over Ribas in view of Kato.
Drawings
New Objection
The drawings are objected to because the numbering of the views throughout the drawings is not in compliance with 37 C.F.R. 1.84(u). For example, the multiple views on pages 1, 2, and 3 are all identified identically as “Fig. 1”. The inclusion of labeling such as “a)” and “b)” next to different images in a view does not distinguish them as partial views. This objection would be resolved by either relabeling each page containing views of the same figure as A, B, C, etc. (for example, page 1 of the drawings filed 14 February 2022 would be FIG. 1A, page 2 would be FIG. 1B, page 3 would be FIG. 1C, page 4 would be FIG. 2A, etc.) or relabeling each image currently identified within pages using a), b), c), etc. as a partial view (for example, page 1 of the drawings filed 14 February 2022 would, when viewed in landscape orientation, have the top row labeled as FIG. 1A and the bottom row labeled as FIG. 1B, page 2 viewed in portrait orientation would have the top row labeled FIG. 1C and the bottom row labeled FIG. 1D, page 3 viewed in landscape orientation would have the top row labeled FIG. 1E and the bottom row labeled FIG. 1F, page 4 viewed in landscape orientation would have the top row labeled FIG. 2A and the bottom row labeled FIG. 2B, etc.). References to the drawings within the specification should also be amended to refer to the correct view or partial view in the corrected drawing sheets. The numbering of views must comply with 37 C.F.R. 1.84(u):
(u) Numbering of views.
(1) The different views must be numbered in consecutive Arabic numerals, starting with 1, independent of the numbering of the sheets and, if possible, in the order in which they appear on the drawing sheet(s). Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter. View numbers must be preceded by the abbreviation "FIG." Where only a single view is used in an application to illustrate the claimed invention, it must not be numbered and the abbreviation "FIG." must not appear.
(2) Numbers and letters identifying the views must be simple and clear and must not be used in association with brackets, circles, or inverted commas. The view numbers must be larger than the numbers used for reference characters. (emphasis added)
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
New Objection
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on page 27 line 11 and line 18 of the specification filed 2 December 2025. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Rejections - 35 USC § 112(b) – Indefiniteness
New Ground of Rejection
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 18-19 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.
Claim 18 is rejected as indefinite because the limitation “wherein (C) comprises administering a checkpoint inhibitor that is a CDK4 inhibitor, a CDK6 inhibitor, or a CDK8 inhibitor” has multiple possible, non-overlapping interpretations for which one of ordinary skill in the art would not be able to discern the intended interpretation and therefore would not understand the metes and bounds of the claim. In a first interpretation, this may be interpreted as replacing step (C) of claim 9 of administering a checkpoint inhibitor to the patient classified as the responder with the limitation in claim 18 (it is noted that a claim directed to this interpretation would be rejected under 35 U.S.C. 112(d) due to not including all limitations of the claim it depends upon; it would also be unclear whether the administration recited in claim 18 is done to the patient classified as the responder, to non-responder patients, or to all patients). In a second interpretation, this may be interpreted as restricting the checkpoint inhibitor recited in claim 9 line 16 to be a CDK4 inhibitor, a CDK6 inhibitor, or a CDK8 inhibitor (it is noted that this interpretation would be made clear by replacing the limitation with “wherein the checkpoint inhibitor is a CDK4 inhibitor, a CDK6 inhibitor, or a CDK8 inhibitor”). In a third interpretation, this may be interpreted as limiting step (C) to comprising both administering a checkpoint inhibitor to the patient classified as the responder and further comprising administering a checkpoint inhibitor that is CDK4 inhibitor, a CDK6 inhibitor, or a CDK8 inhibitor to an unspecified patient (in this interpretation, it is further unclear whether this is administered to the patient classified as the responder, to non-responder patients, or to all patients). For the purpose of examination, the second interpretation of the limitation restricting the checkpoint inhibitors recited in claim 9 line 16 is used.
Claim 19 is rejected as indefinite because the limitation “wherein (C) comprises administering a checkpoint inhibitor that is an anti-CTLA-4 monoclonal antibody, an anti-PD-1 monoclonal antibody, or an anti PD-L1 antibody” has multiple possible, non-overlapping interpretations for which one of ordinary skill in the art would not be able to discern the intended interpretation and therefore would not understand the metes and bounds of the claim. The possible interpretations are analogous to those described for claim 18 above. For the purpose of examination, the second interpretation of the limitation restricting the checkpoint inhibitors recited in claim 9 line 16 is used.
Claim Rejections - 35 USC § 112(a) - New Matter
New Ground of Rejection
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 18 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Claim 18 was first added in the preliminary amendment to the claims filed 16 August 2022 after the filing date of the application (14 February 2022) and is unchanged in the current claims as filed 2 December 2025. Claim 18 recites administering a checkpoint inhibitor that is a CDK4 inhibitor, a CDK6 inhibitor, or a CDK8 inhibitor. As discussed in the rejection of claim 18 under 35 U.S.C. 112(b) above, the claim is interpreted as limiting the checkpoint inhibitors administered to the patient classified as the responder to being a CDK4 inhibitor, a CDK6 inhibitor, or a CDK8 inhibitor. The only mention of treatment, therapy, administration of inhibitors of CDK4, CDK6, or CDK8 in the disclosure of the application on its filing date is in the specification in paragraph [0026]: “The invention also allows the conclusion that a patient who is non-responsive to checkpoint inhibitor therapy may preferably be alternatively or additionally (combination therapy) subjected to a treatment with directly senescence-inducing compounds like CDK4 inhibitors and/or CDK 6 inhibitors and/or CDK8 inhibitors”. As the disclosure only discloses treating patients non-responsive to checkpoint inhibitor therapy with CDK4 inhibitors, CDK6 inhibitors, or CDK8 inhibitors, claim 18 claiming administration of CDK4 inhibitors, CDK6 inhibitors, or CDK8 inhibitors to the patient classified as a responder (to checkpoint inhibitor therapy) claims subject matter that is not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor.
Claim Rejections - 35 USC § 112(a) - Scope of Enablement
New Ground of Rejection
The text of those sections of Title 35, U.S. Code not included in this section can be found in the 35 U.S.C. 112(a) - New Matter rejection above.
Claims 1-11, 13, and 16-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of classifying a patient in need as a non-responder or a responder to immune checkpoint inhibitor therapy and a method of treatment of a patient comprising such classifying when the patient is a human patient suffering from cancer, does not reasonably provide enablement for any non-human patients or for human patients that do not have cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
Scope of the Claims/Nature of the Invention
The claims are drawn to methods of classifying a patient in need as a non-responder or responder to immune checkpoint inhibitor therapy or of treatment that includes such classification. In view of the recitation of “patient in need” in claim 1 and [0016] of the specification defining a patient in need as referring “to any kind of living being, including a human or animal, such as a tumor patient, which may benefit from checkpoint inhibitor therapy”, claims 1-2 and 4-5 broadly encompass ANY living being that may or may not be diseased since any being may potentially benefit from checkpoint inhibitor being administered. In view of the recitation of “metastatic melanoma” in claim 6, claim 6 broadly encompasses ANY living being suffering from metastatic melanoma, not just humans. In view of the recitation of “metastatic carcinoma” and “lymphoma” in claims 7 and 8, respectively, claims 7 and 8 broadly encompass ANY living being suffering from the respective disease. In view of the recitation of “a cancer patient” in claim 9, claims 9-10, 13, 16, and 18-19 broadly encompass ANY living being having any type of cancer. In view of the recitation “said patient is suffering from a metastatic melanoma, a metastatic carcinoma, or a lymphoma” in claim 17, claim 17 broadly encompasses ANY living being suffering from a metastatic melanoma, metastatic carcinoma, or a lymphoma.
The nature of the invention as most broadly claimed (claims 1-2 and 4-5) requires a correlation between the responder status of ANY type of patient (which may or may not have a cancer) and the presence or absence of genetic alterations in cell cycle regulator genes that are cellular senescence-inducing or -inhibiting.
Teachings in the Specification and Examples
In the Examples section, the specification teaches in [00102] the identification of specific senescence-inducing cell cycle genes and specific genes promoting cell cycle progression (senescence-inhibiting cell cycle genes) that are associated with immune checkpoint inhibitory therapy response in human melanoma patients (the patients are presumed to be human based on the description of the patients in [0088], since no standard cancer model organism lives to ages up to 89 years and only humans can sign written informed consent forms). The specification further defines patients in need as any kind of living being which may benefit from checkpoint inhibitor therapy in [0016] and asserts that the invention is applicable to patients suffering from carcinoma or lymphoma in [0060].
State of the Art and Unpredictability of the Art
The claims broadly encompass being able to classify any patient in need as a non-responder or responder to immune checkpoint inhibitor therapy, wherein the patient may be any living organism with or without disease. The prior art teaches that there is a large amount of unpredictability with regard to comparing results from gene expression analysis in humans to even closely related animals. For example, Coleman (“Of mouse and man – what is the value of the mouse in predicting gene expression in humans?” Drug Discov Today, 8(6) pages 233-235 (2003)) found that while gene expression patterns between mice and humans shared some degree of similarity, the basic patterns of gene expression differed and that there was no general rule for predicting gene expression (page 2, paragraph 3 through page 3). Coleman concluded that “The validity of mouse or other animal species as a human surrogate should not be assumed.” These teachings of Coleman support the finding that there is no predictable means for determining whether the presence of specific genetic alterations that are predictive of immune checkpoint inhibitor therapy responsiveness in a human subject will also be predictive of immune checkpoint inhibitor therapy responsiveness in non-human subjects.
Prior art such as that of Ribas et al. (US Patent Document Cite No. A2 in IDS filed 27 May 2022)(US 2018/0051347, published 22 February 2018, effectively filed 12 July 2016) teaches the association of cell cycle regulator genes with immune checkpoint inhibitor therapy response in various cancers (“melanoma, skin cutaneous melanoma, non-small cell lung cancer, colon cancer, endometrial cancer, kidney cancer, bladder cancer, Merkel cell carcinoma, Hodgkin lymphoma, breast invasive carcinoma, prostate adenocarcinoma, lung adenocarcinoma, or colorectal adenocarcinoma” [0029]). Therefore, one of ordinary skill in the art would be reasonably enabled to practice the claimed invention in humans suffering from cancers other than melanoma. However, the art does not enable practicing the claimed invention for non-cancer disease in humans or for any non-humans.
Quantity of Experimentation
The quantity of experimentation necessary to enable the full scope of the claims is undue and one of ordinary skill in the art would have little if any reasonable expectation of success in achieving enablement of the full scope of the claims. In support of this position, it is noted that the claimed methods encompass being able to classify ANY human, regardless of having cancer or not, or non-human living being as a non-responder or responder to immune checkpoint inhibitor therapy based on the presence or absence of a genetic alteration in cellular senescence-inducing or -inhibiting cell cycle regulator genes. In order to practice the breadth of the claimed invention one of ordinary skill in the art would first have to identify human and non-human living beings having various conditions (no disease, various cancer types, various other diseases) that are responders or non-responders to immune checkpoint inhibitor therapy to be sufficiently representative of all human and non-human living beings that are responders or non-responders, which would involve treating the many such living beings with immune checkpoint inhibitor therapy and tracking their responses. Then samples would need to be obtained from all of the living beings identified above. Then the presence of alterations of cellular senescence-inducing or -inhibiting cell cycle regulator genes would need to be analyzed and correlated with whether the living being responded to immune checkpoint inhibitor therapy. The specification has not done any of the above aside from executing this with human melanoma patients. The results of such experimentation are highly unpredictable, since the art discussed above indicates that genetic markers vary among even closely related species of living being. The amount of experimentation that would be required to practice the full scope of the claimed invention and the amount of time and cost this experimentation would take therefore supports the position that such experimentation is undue (see MPEP §2164.06).
Conclusions
Herein, although the level of ordinary skill in the art is high, given the lack of disclosure in the specification and in the prior art and the unpredictability of the art, it would require undue experimentation for one of ordinary skill in the art to make and use the full scope of the invention as broadly claimed in claims 1-11, 13, and 16-19.
Claim Rejections - 35 USC § 101
Modified, New Ground of Rejection
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 1-11, 13, and 16-19 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. While the claims are directed to a process, and therefore meet step 1 of the subject matter eligibility test (see MPEP §2106.03), the claim(s) recite(s) the abstract ideas of classifying patients based on genetic condition (claim 1 step 3 and claim 9 step A3) and determining an absence of a genetic alteration (claim 9 step B), which are mental processes because they can be done in the human mind looking at data gathered by analyzing the biological sample for the presence or absence of the genetic alterations and drawing conclusions regarding the absence of a genetic alteration and the classification of the patient (from claim 1 steps 1-2 and claim 9 steps A1-A2).
Step 2A of the subject matter eligibility test require a two-pronged analysis. Prong One asks: does the claim recite an abstract idea, law of nature or natural phenomenon? As discussed in MPEP §2106.04(II)(A)(1), the meaning of “recites” is “set forth” or “describes”. That is, a claim recites a judicial exception when the judicial exception is “set forth” or “described” in the claim. In the instant case, the claims describe the abstract ideas of classifying patients based on genetic condition and determining an absence of a genetic alteration.
Prong Two of the analysis under step 2A asks: does the claim recite additional elements that integrate the judicial exception into a practical application of the judicial exception? As discussed in MPEP §2106.04(II)(A)(2):
Because a judicial exception is not eligible subject matter, Bilski, 561 U.S. at 601, 95 USPQ2d at 1005-06 (quoting Chakrabarty, 447 U.S. at 309, 206 USPQ at 197 (1980)), if there are no additional claim elements besides the judicial exception, or if the additional claim elements merely recite another judicial exception, that is insufficient to integrate the judicial exception into a practical application. See, e.g., RecogniCorp, LLC v. Nintendo Co., 855 F.3d 1322, 1327, 122 USPQ2d 1377 (Fed. Cir. 2017) ("Adding one abstract idea (math) to another abstract idea (encoding and decoding) does not render the claim non-abstract"); Genetic Techs. Ltd. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016) (eligibility "cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself."). For a claim reciting a judicial exception to be eligible, the additional elements (if any) in the claim must "transform the nature of the claim" into a patent-eligible application of the judicial exception, Alice Corp., 573 U.S. at 217, 110 USPQ2d at 1981, either at Prong Two or in Step 2B.
The considerations to be used are set forth in MPEP §2106.04(d)(2) and MPEP §2106.05(a) through (c) and (e) through (h). Turning to those sections of the MPEP:
MPEP §2106.05(a) has to do with improvements to the functioning of a computer or to any other technology or technical field. The claims at issue do not improve the functioning of a computer.
MPEP §2106.05(b) has to do with whether the claims involve the use of a particular machine. In this case, the claims do not involve the use of a particular machine as all materials used in steps of the method are described generically.
MPEP §2106.05(c) has to do with whether the claims involve a particular transformation. Here, the claims do not involve a particular transformation because the claims are for a process.
MPEP §2106.05(e) has to do with “other meaningful limitations”. The additional limitations imposed upon the abstract ideas consist of: (1) providing a biological sample, (2) analyzing the biological sample for the presence or absence of a genetic alteration causing a modification of function in cell cycle regulator genes that affect cellular senescence (claim 1 steps 1-2, claim 9 steps A1-A2 and claims dependent on them), (3) limiting the alteration and gene to mutations in specific genes (claims 3-4, 11, 13, and 16), (4) limiting a disease the patient is suffering from (claims 6-9 and 17 and claims dependent on them), (5) administering a checkpoint inhibitor (claim 9 and claims dependent on it), and (6) limiting the checkpoint inhibitor to specific classes of therapeutic (claims 18 and 19, see 35 U.S.C. 112(b) rejection regarding their interpretation for the purpose of examination). These are not considered meaningful limitations because limitations (1-6) generally link the use of the judicial exceptions to the particular technological environment of immune checkpoint inhibitor therapy.
MPEP §2106.04(d)(2) has to do with whether the additional elements apply or use the judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition. While the recited limitations (5-6) are treatment steps, they are not considered to apply or use the judicial exception to effect a particular treatment. The treatment step (claim 9 step C) occurs within a contingent limitation because the checkpoint inhibitor is administered only to patients classified as responders, whereas the method is applied generally to cancer patients who have not received checkpoint inhibitor therapy. MPEP §2111.04 II. states: “The broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met”. As some cancer patients will be classified as non-responders (see instant specification [0007]), the method can be performed without a treatment step in the case where the patient is classified as a non-responder in step A3, and so the broadest reasonable interpretation of the method of claims 9-10, 13, and 16-19 is not limited by steps B and C of claim 9 that only occur when the patient is a responder. Since the method claimed encompasses methods where no treatment is administered, the judicial exception is not applied to effect a particular treatment.
MPEP §2016.05(f) raises the question as to whether the additional elements recited in the claim represent “mere instructions to apply an exception”. As limitations (1-4) are either data gathering used by the abstract ideas or limit said data gathering, and limitations (5-6) do not limit the scope of the claims as discussed above, the additional elements represent mere instructions to apply the exceptions.
MPEP §2106.05(g) has to do with whether the additional elements of the claim amount to insignificant extra-solution activity. MPEP §2106.05(g) notes that “[d]etermining the level of a biomarker in blood” is an example of “mere data gathering” which the courts have found to be insignificant extra-solution activity. Therefore, the limitations (1-4) are the mere gathering of data representing the presence or absence of genetic alteration(s) that is used in the abstract ideas, and limitations (5-6) do not limit the scope of the claims as discussed above, so the additional elements amount to insignificant extra-solution activity.
MPEP §2106.05(h) has to do with whether the additional elements amount to more than generally linking the use of a judicial exception to a particular technological environment or field of use. The recitation of the judicial exceptions being applied to classifying the responder status of patients to immune checkpoint inhibitor therapy represent “field of use” limitations. However, as MPEP §2106.05(h) indicates, such limiting to a particular “field of use” does not confer patentability to otherwise ineligible subject matter.
In addition, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception (as set forth in step 2B of the subject matter eligibility test) because it was known in the prior art to analyze biological samples for genetic alterations, as seen in the prior art of Ribas et al. (US Patent Document Cite No. A2 in IDS filed 27 May 2022)(US 2018/0051347, published 22 February 2018, effectively filed 12 July 2016, see 35 U.S.C. 103 rejection of claim 1 below for full mapping of limitations).
Having considered the factors discussed in MPEP §2106.05 as well as the prior art of Ribas et al., it is clear that the additional elements recited in the claims, whether considered individually or as a combination, do not integrate the judicial exceptions into a practical application of those exceptions in such a way as to provide meaningful limits on the use of the judicial exception and do not amount to significantly more than the judicial exception. Therefore, claims 1-11, 13, and 16-19 are rejected here under 35 U.S.C. 101.
Response to Arguments
Applicant’s arguments, see pages 10-15 of the remarks, filed 2 December 2025, with respect to the rejection(s) of claim(s) 1-2, 4-10, 12, 13, and 15-19 under 35 U.S.C. 101 have been fully considered and are persuasive in-part, as delineated below. On pages 10-11 of the remarks, applicant summarizes the rejection of the previous Office Action.
With regard to Applicant’s argument on the middle paragraph of page 11 of the remarks that the claims are not directed to a “law of nature”, the argument is persuasive. Insofar as the rejection is for having claims directed to a law of nature, the rejection is withdrawn. However, as far as this paragraph further asserts that the claims are not directed to an abstract idea, the argument is not persuasive because it does not provide any clear argument for why the classification of patients based on genetic condition datasets is not an abstract idea that the claims are directed to. Therefore, insofar as the rejection is for having claims directed to an abstract idea, the rejection is not withdrawn.
With regard to Applicant’s argument on the last paragraph of page 11 of the remarks that the claimed method requires various tangible operations that go beyond observation and produce a dataset, thereby integrating the abstract idea judicial exceptions (as far as the law of nature/natural correlation judicial exception the argument is moot due to the previous paragraph being persuasive regarding it), the argument is not persuasive because the operations and production of a dataset described are data gathering that amounts to insignificant extra-solution activity because they are analogous to determining the level of a biomarker, which is described in MPEP §2106.05(g) as an example of insignificant extra-solution activity.
With regard to Applicant’s argument on pages 12-15 of the remarks that the Office Action mailed 11 June 2025 gives no weight to the treatment step of claim 9 and fails to discuss its effect on the patent eligibility analysis, the argument is persuasive. However, as described in the new rejection under 35 U.S.C. 101, while claims 9-11, 13, and 16-19 are directed to a method of treatment they do not require the administration of a particular treatment because the administration step is within a contingent limitation that is not necessary for the method of claims 9-11, 13, and 16-19 to be practiced.
Therefore, the rejection has been modified and is a new ground of rejection.
Claim Rejections - 35 USC § 102
New Ground of Rejection
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 5-11, 17-19 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Ribas et al. (US Patent Document Cite No. A2 in IDS filed 27 May 2022)(US 2018/0051347, published 22 February 2018, effectively filed 12 July 2016), herein Ribas.
Regarding claim 1, Ribas teaches an ex vivo method for classifying a patient in need as a non-responder or a responder to immune checkpoint inhibitor therapy ([0020-0021], teaching determination of whether a subject is a candidate for the immune checkpoint therapies anti-PD-1, anti-PD-L1, and anti-CTLA-4 therapy, equivalent to the claimed responder, or an alternative therapy to the immune checkpoint therapies, equivalent to the claimed non-responder), comprising the following steps:
providing a biological sample originating from said patient (“step (a) comprises obtaining a sample from the cancer” [0021]; “a method of assessing a subject having cancer” [0020]);
analyzing the biological sample for the presence or absence of a genetic alteration causing a modification of function in
cellular senescence-inducing cell cycle regulator gene(s) (“(a) determining or having determined whether the cancer comprises a loss of function mutation or disruption in an interferon signaling pathway” [0020]; “the loss of function mutation or disruption in an interferon signaling pathway is a mutation or disruption that truncates a Janus kinase 1 (JAK1) or a Janus kinase 2 (JAK2) protein” [0022], JAK1 and JAK2 are inherently cellular senescence-inducing cell cycle regulator genes as is stated in instant claim 3 and instant specification [0031, 0041, and 0042]), or
cellular senescence-inhibiting cell cycle regulator gene(s),
classifying the patient as
non-responder if, in step (2), said genetic alterations are identified as present (“the subject is a candidate for: […] an alternative therapy to that of an anti-PD-1 therapy, an anti-PD-L1 therapy, an anti-CTLA-4 therapy, or a combination thereof when the cancer is positive for at least one loss of function mutation or disruption in an interferon signaling pathway” [0020]), or
responder if, in step (2), said genetic alterations are identified as absent (“the subject is a candidate for: an anti-PD-1 therapy, an anti-PD-L1 therapy, an anti-CTLA-4 therapy, or a combination thereof when the cancer is negative for a loss of function mutation or disruption in an interferon signaling pathway” [0020], note that determining candidacy for anti-PD-1/PD-L1/CTLA-4 therapy or for an alternative therapy are considered equivalent to determining that the patient is likely to respond to or benefit from the respective therapy).
Regarding claim 2, Ribas teaches the method of claim 1 (see 35 U.S.C. 102 rejection of claim 1 above), wherein said genetic alteration causing a modification of function is a
loss-of-function mutation in cellular senescence-inducing cell cycle regulator gene(s) (“the loss of function mutation or disruption in an interferon signaling pathway is a mutation or disruption that truncates a Janus kinase 1 (JAK1) or a Janus kinase 2 (JAK2) protein” [0022]), or
gain-of-function mutation in cellular senescence-inhibiting cell cycle regulator gene(s).
Regarding claim 3, Ribas teaches the method of claim 2 (see 35 U.S.C. 102 rejection of claim 2 above), wherein said genetic alteration is the loss-of-function mutation, and wherein said cellular senescence-inducing cell cycle regulator genes are one or more genes selected from the groups consisting of: JAK1 and JAK2, which are the species examined in addition to the elected species, see Election/Restriction section above (“the loss of function mutation or disruption in an interferon signaling pathway is a mutation or disruption that truncates a Janus kinase 1 (JAK1) or a Janus kinase 2 (JAK2) protein” [0022]; “the singular forms “a,” “an” and “the” include plural referents” [0125], so [0022] also teaches the method wherein both JAK1 and JAK2 are selected).
Regarding claim 5, Ribas teaches the method of claim 1 (see 35 U.S.C. 102 rejection of claim 1 above), wherein said step (3) said classification as a non-responder occurs if a genetic modification is identified as present in at least 1 cellular senescence-inducing cell cycle regulator gene(s) or senescence-inhibiting cell cycle regulator genes (“the subject is a candidate for: […] an alternative therapy to that of an anti-PD-1 therapy, an anti-PD-L1 therapy, an anti-CTLA-4 therapy, or a combination thereof when the cancer is positive for at least one loss of function mutation or disruption in an interferon signaling pathway” [0020]).
Regarding claim 6, Ribas teaches the method of claim 1 (see 35 U.S.C. 102 rejection of claim 1 above), wherein said patient is suffering from a metastatic melanoma (“In some aspects, the cancer is melanoma, skin cutaneous melanoma” [0029]; “In some embodiments, melanoma is metastatic” [0129]; “JAK Loss-of-Function Mutations in Primary Resistance to PD-1 Blockade in Patients with Metastatic Melanoma” [0290]).
Regarding claim 7, Ribas teaches the method of claim 1 (see 35 U.S.C. 102 rejection of claim 1 above), wherein said patient is suffering from a metastatic carcinoma (“In some aspects, the cancer is […] Merkel cell carcinoma, […] breast invasive carcinoma, prostate adenocarcinoma, lung adenocarcinoma, or colorectal adenocarcinoma” [0029]; “JAK Loss-of-Function Mutations in Primary Resistance to PD-1 Blockade in Patients with Metastatic Colon Carcinoma” [0297]).
Regarding claim 8, Ribas teaches the method of claim 1 (see 35 U.S.C. 102 rejection of claim 1 above), wherein said patient is suffering from a lymphoma (“In some aspects, the cancer is […] Hodgkin lymphoma” [0029]).
Regarding claim 9, Ribas teaches a method of treatment (“the method further comprises (c) administering a therapy”) comprising:
(1) providing a biological sample originating from a cancer patient who has not received checkpoint inhibitor therapy (“a subject having cancer” [0020]; “obtaining a sample from the cancer” [0021]; “In some aspects, the subject has not previously been administered an anti-PD-1 therapy, an anti-PD-L1 therapy, an anti-CTLA-4 therapy, or a combination thereof” [0030]);
the limitations of steps (A)(2) and (A)(3) in claim 9 are functionally equivalent to steps (2) and (3) in claim 1 and the same teachings of Ribas apply (see 35 U.S.C. 102 rejection of claim 1 above);
(B) determining an absence of said genetic alteration(s) in the biological sample and classifying the patient as a responder (“(b) determining or having determined from the results of (a) that the subject is a candidate for: an anti-PD-1 therapy, an anti-PD-L1 therapy, an anti-CTLA-4 therapy, or a combination thereof when the cancer is negative for a loss of function mutation or disruption in an interferon signaling pathway” [0020]; note that though this limitation is taught by Ribas, the broadest reasonable interpretation of claim 9 does not require this limitation because it is contingent on said genetic alterations being absent, which the method can be practiced without in the case of the patient being a non-responder, see MPEP §2111.04 II.); and
(C) administering a checkpoint inhibitor to the patient classified as the responder (“the method further comprises (c) administering a therapy to the subject based on the results of step (b)” [0021]; note that though this limitation is taught by Ribas, the broadest reasonable interpretation of claim 9 does not require this limitation because it is contingent on said genetic alterations being absent and the patient being classified as a responder, which the method can be practiced without in the case of the patient being a non-responder, see MPEP §2111.04 II.)
Regarding claim 10, Ribas teaches the method of claim 9 (see 35 U.S.C. 102 rejection of claim 9 above). The further limitation of step (A)(2) recited in claim 10 is functionally equivalent to the further limitation of claim 1 by claim 2 and the same teachings of Ribas apply (see 35 U.S.C. 102 rejection of claim 2).
Regarding claim 11, Ribas teaches the method of claim 10 (see 35 U.S.C. 102 rejection of claim 10 above). The further limitation of step (A)(2) recited in claim 11 is functionally equivalent to the further limitation of claim 2 by claim 3 and the same teachings of Ribas apply (see 35 U.S.C. 102 rejection of claim 3).
Regarding claim 17, Ribas teaches the method of claim 1 (see 35 U.S.C. 102 rejection of claim 1 above), wherein said patient is suffering form a metastatic melanoma, a metastatic carcinoma, or a lymphoma (see 35 U.S.C. 102 rejections of claim 6-8 above reciting these cancers).
Regarding claim 18, Ribas teaches the method according to claim 10 (see 35 U.S.C. 102 rejection of claim 10 above). Note that though Ribas does not teach administering a checkpoint inhibitor to the patient classified as the reporter wherein the checkpoint inhibitor is a CDK4 inhibitor, a CDK6 inhibitor, or a CDK8 inhibitor (see 35 U.S.C. 112(b) rejection of claim 18 regarding why claim 18 is interpreted this way), the broadest reasonable interpretation of claim 18 does not require this limitation because it is contingent on said genetic alterations being absent and the patient being classified as a responder, which the method can be practiced without in the case of the patient being a non-responder, see MPEP §2111.04 II. Therefore, Ribas teaches all limitations that are required of the method of claim 18.
Regarding claim 19, Ribas teaches the method according to claim 10 (see 35 U.S.C. 102 rejection of claim 10 above), wherein (C) comprises administering a checkpoint inhibitor that is an anti-CTLA-4 monoclonal antibody, an anti-PD-1 monoclonal antibody, or an anti PD-L1 antibody (see 35 U.S.C. 112(b) rejection above regarding the interpretation of claim 19; “the method further comprises (c) administering a therapy to the subject based on the results of step (b)” [0021]; “determining or having determined from the results of (a) that the subject is a candidate for: an anti-PD-1 therapy, an anti-PD-L1 therapy, an anti-CTLA-4 therapy, or a combination thereof when the cancer is negative for a loss of function mutation or disruption in an interferon signaling pathway” [0020]). Note that though this limitation is taught by Ribas, the broadest reasonable interpretation of claim 19 does not require this limitation because it is contingent on said genetic alterations being absent and the patient being classified as a responder, which the method can be practiced without in the case of the patient being a non-responder, see MPEP §2111.04 II.
Therefore, claims 1-3, 5-11, and 17-19 are anticipated by Ribas.
Claim Rejections - 35 USC § 103
Modified, New Ground of Rejection
Claims 4, 13, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Ribas et al. (US Patent Document Cite No. A2 in IDS filed 27 May 2022)(US 2018/0051347, published 22 February 2018, effectively filed 12 July 2016), herein Ribas, as applied to claims 1-3, 5-11, and 17-19 above, and in view of Kato et al. (“Analysis of MDM2 Amplification: Next-Generation Sequencing of Patients With Diverse Malignancies” JCO Precis Oncol 2, pages 1-14 (2018)), herein Kato.
Regarding claim 4, Ribas teaches the method of claim 2 (see 35 U.S.C. 102 rejection of claim 2 above). However, Ribas does not teach that the alteration is a gain-of-function mutation or wherein the cellular senescence-inhibiting cell cycle regulator gene is the elected species MDM2. This deficiency is made up for in the teachings of Kato.
Regarding claim 4, Kato teaches that amplification (a type of gain-of-function mutation) of MDM2 is a marker for accelerated tumor growth when patients are treated with immune checkpoint inhibitors (“MDM2 amplification also has been implicated as a potential marker for accelerated tumor growth with receipt of immune checkpoint inhibitors” Kato page 2 left column paragraph 3; “the remaining part of patients develops a tumor progression many of within three months of immune therapy. Such patients are referred to as non-responders” instant specification [0007], so the patients taught by Kato with accelerated tumor growth are non-responders as the term is used in the instant application). By substituting the genetic alteration of the gain-of-function mutation of MDM2 for the loss of function mutation in an interferon signaling pathway in the method of Ribas, the combination of Ribas and Kato teach the method of claim 4.
Regarding claim 13, Ribas teaches the method of claim 10 (see 35 U.S.C. 102 rejection of claim 10 above). The further limitation of step (A)(2) recited in claim 13 is functionally equivalent to the further limitation of claim 2 by claim 4 and the same teachings of Kato apply (see 35 U.S.C. 103 rejection of claim 4 above).
Regarding claim 16, Ribas teaches the method of claim 10 (see 35 U.S.C. 102 rejection of claim 10 above). The further limitation of step (A)(2) recited in claim 16 as interpreted in the Office Action mailed 11 June 2025 (that step (A)(2) comprises analyzing the biological sample for a gain-of-function mutation in MDM2) is functionally equivalent to the further limitation of claim 2 by claim 4 and the same teachings of Kato apply (see 35 U.S.C. 103 rejection of claim 4 above).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to perform the simple substitution of the genetic alteration of the gain-of-function mutation of MDM2, as taught by Kato, for the loss of function mutation in an interferon signaling pathway in the method of Ribas, because (MPEP §2143 I. B.). One of ordinary skill in the art could have performed this substitution and would have found the results of this substitution predictable because the teachings of Kato and Ribas recognized these genetic alterations as having the same association of being associated with patients that do not positively respond to immune checkpoint inhibitor therapy and therefore would be expected to provide similar predictive value. Therefore, the invention as a whole of claims 4, 13, and 16 would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention.
Response to Arguments
Applicant’s arguments with respect to claim(s) 1-2, 5-10, and 17-19 have been considered. With regard to the argument in the paragraph on pages 8 and 9 of the remarks that Galon teaches a mutation that is predictive of a response, in contrast to the claim being for mutations that are predictive of non-response and the absence of the mutations being predictive of response, the argument is persuasive. As Spetzler does not cure this deficiency, the 35 U.S.C. 103 rejections of the Office Action mailed 11 June 2025 are withdrawn and remaining arguments are moot. However, upon further consideration, new grounds of rejection are made over Ribas and Ribas in view of Kato.
While the declaration under 37 CFR 1.132 has been considered, an allegation of unexpected results is unable to overcome a 35 U.S.C. 102 rejection. Regarding the new 35 U.S.C. 103 rejections, the declaration does not compare the nearest prior art of the combination of Ribas and Kato with the claimed subject matter as required by MPEP §716.02(e). Additionally, the allegation of unexpected results is not commensurate with the scope of the claims rejected under 35 U.S.C. 103, as required by MPEP §716.02(d), because the results discussed are obtained only in patients that appear to be human and that have melanoma. The scope of claim 4 encompasses classifying any patient in need, which may be human or non-human and with or without any disease, and the scope of claims 13 and 16 encompass classifying any cancer patient, which may be human or non-human.
Conclusion
Claims 1-11, 13, and 16-19 are rejected. Claims 12 and 14-15 are withdrawn. No claims are allowed.
This action is NON-FINAL.
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/JEFFREY BELLAH/Examiner, Art Unit 1683
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683
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