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 Amendment
Claims 2 and 4 have been cancelled. All of the claims, Claims 1, 3, 5-15 have been amended as requested in the amendment filed on 15 September 2025. Following the amendment, claims 1, 3, and 5-15 are pending in the instant application, and are under examination in the instant office action.
Claim Rejections - 35 USC § 112 (Maintained in part)
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 12/13 stands as 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, for reasons of record in the previous Office action.
Claim 12 remains indefinite wherein it recites “using” without setting forth any steps involved in the process(es). MPEP 2173.05(q)) states: Attempts to claim a process without setting forth any steps involved in the process generally raises an issue of indefiniteness under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph. The instant claim recites, “wherein the complex is detected using a secondary antibody against IgG”, which is the same fact pattern as the claim in Ex parte Erlich, 3 USPQ2d 1011 (Bd. Pat. App. & Inter. 1986), which read: "[a] process for using monoclonal antibodies of claim 4 to isolate and purify human fibroblast interferon". The claim in Ex parte Erlich was held to be indefinite because it merely recites a use without any active, positive steps delimiting how this use is actually practiced. Therefore, Claim 12 is rejected, and this affects the scope of dependent claim 13.
Claim Rejections - 35 USC § 112 (New, Necessitated by Amendment)
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.
As currently amended to recite treating cancer comprising administering a therapeutically effective amount of an immune checkpoint inhibitor, Claims 1, 3 and 5-15 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 determining a level of an anti-PD1 antibody autoantibody (AAb) in a blood sample; wherein detection of an elevated level relative to control is indicative that the patient has head and neck squamous cell carcinoma (HNSCC; see Figs. 1 and 2), and treating comprising administering the specific checkpoint inhibitor (CPI), atezolizumab (specification pgs. 6 and 13); the specification does not reasonably provide enablement for determining the presence of any other cancer comprising detecting elevated anti-PD1 AAb and treating any other cancer comprising administering any CPI. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure would require undue experimentation include:
A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims
With respect to claim breadth, the standard under 35 U.S.C. §112, first paragraph, entails the determination of what the claims recite and what the claims mean as a whole. In addition, when analyzing the scope of enablement, the claims are analyzed with respect to the teachings of the specification and are to be “given their broadest reasonable interpretation consistent with the specification.” See MPEP 2111 [R-5]; Phillips v. AWH Corp., 415 F.3d 1303, 75 USPQ2d 1321 (Fed. Cir. 2005); and In re Hyatt, 211 F.3d 1367, 1372, 54 USPQ2d 1664, 1667 (Fed. Cir. 2000). Applicant always has the opportunity to amend the claims during prosecution, and broad interpretation by the examiner reduces the possibility that the claim, once issued, will be interpreted more broadly than is justified. In re Prater, 415 F.2d 1393, 1404-05, 162 USPQ 541, 550- 51 (CCPA 1969).
As such, the broadest reasonable interpretation of the claimed method is that it provides treatment for any cancer comprising detecting anti-PD-1 autoantibodies and administering any immune checkpoint inhibitor. A skilled artisan would not know how to use the method with a reasonable expectation of success based solely on what is disclosed in the specification.
The amount of direction and existence of working examples
What is enabled by the working examples is narrow in comparison to the breadth of the claims: The specification discloses anti-PD1 antibody levels are in serum samples of head and neck squamous carcinoma cell (HNSCC) patients with tumors before the beginning of atezolizumab treatment. These levels in HNSCC samples are elevated relative to the levels in healthy donors and tumor-free HNSCC patients after atezolizumab treatment (Figures 1 and 2). There is no evidence in the disclosure as filed that anti-PD1 autoantibodies are elevated in the serum of cancer patients other than those having HNSCC.
The state of the prior art
The presence of specific autoantibodies (AAbs) in cancer patients was well-established in the art prior to filing (Zaenker et al. Autoimmunity Reviews, 15: 477-483, (2016). Zaenker et al. state: “Since tumors originate from autologous cells containing self-antigens, it has been suggested that it is the abnormal exposure or presentation of these antigens that facilitates an autoimmune response. Over the last few decades, AAbs have become of particular interest as cancer biomarkers as they can be easily extracted from serum via minimally invasive blood collection. Moreover, they exhibit increased levels in very early cancer stages and are observed in patients with several carcinomas, including breast [4], lung [5], gastrointestinal [3], ovarian, and prostate. What is more, their production may precede clinical confirmation of a tumor by several months or years.” (pg. 478, Introduction, first two paragraphs, citations removed). The authors teach autoimmune responses, such as the production of autoantibodies, may be part of a chronic inflammatory response toward cancer cells and are associated with an array of immunological pathways (pg. 479 at bullet 2.3). Along these lines, elevated anti-PD1 autoantibodies were detected in the serum of patients with the chronic autoimmune disease Lupus (SLE) (see Shi et al. art of record). However, Zaenker et al. emphasize that particular cancers are associated with particular AAbs against specific antigens. There was nothing within the art at the time before the effective filing date of the instant application, that taught or suggested that elevated serum anti-PD1 AAbs were indicative of all cancers. The instant specification teaches anti-PD1 AAbs are associated with HNSCC cancer only and it would take further experimentation in order to validate that the invention could be used to indicate all other cancers.
The level of one of ordinary skill in the art of detecting and treating cancer is high. One of ordinary skill would have to be a board certified Oncologist.
The level of predictability in the art
The level of predictability, even within the current art of record, remains low. The following post-filing references demonstrate much unpredictability still exists between the presence of anti-PD1 AAbs and the ability of checkpoint inhibitors to treat cancer. While some post-filing studies demonstrate the anti-PD1 AAb IgG4 subclass was identified to associate with overall survival, and may serve as a potential biomarker for anti-PD1 therapeutic survival benefit specifically in NSCLC patients (Tan et al., Cancer Immunology, Immunotherapy, 71: 1681-1691, 2022; Abstract Conclusion), other post-filing studies demonstrate the exact opposite effect. The following reference teaches PD1 AAbs were significantly increased in patients that were non-responders to checkpoint inhibitors (Tan et al., Theranostics, 10(14): 6399-6410, 2020). Therefore, even within the current literature much unpredictability exists between the presence of anti-PD1 AAbs and successful treating comprising administering checkpoint inhibitors (CPI) as claimed. The specification teaches only one specific embodiment - successful treatment of HNSCC with the specific CPI, atezolizumab (Figures 1 and 2), which does not overcome the unpredictability within the art. Absent evidence in the specification that anti-PD1 AAbs are predictive of successful CPI treatment over cancers on the whole, then the invention is not enabled commensurate in scope with the breadth of the claims.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success. A patent is granted for a completed invention, not the general suggestion of an idea and how that idea might be developed into the claimed invention. In the decision of Genentech, Inc, v. Novo Nordisk, 42 USPQ 2d 1001, (CAFC 1997), the court held that:
"[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable" and that "[t]ossing out the mere germ of an idea does not constitute enabling disclosure". The court further stated that "when there is no disclosure of any specific starting material or of any of the conditions under which a process is to be carried out, undue experimentation is required; there is a failure to meet the enablement requirements that cannot be rectified by asserting that all the disclosure related to the process is within the skill of the art", "[i]t is the specification, not the knowledge of one skilled in the art, that must supply the novel aspects of an invention in order to constitute adequate enablement".
The instant specification is not enabling because one cannot follow the guidance presented therein, or within the art at the time of filing, and practice the claimed method, with a reasonable expectation of successfully treating cancer, without first making a substantial inventive contribution.
The nature of the invention
The nature of the invention is directed to in vivo treatment of cancer, in general, comprising administering a therapeutically effective amount of an immune checkpoint inhibitor to the subject, if the level of the anti-PD1 autoantibody is determined to be elevated relative to a control level. The specification has provided enabling guidance that elevated anti-PD1 AAbs indicate only one specific type of cancer (HNSCC) and demonstrate successful treatment by a specific CPI, atezolizumab, in this specific cohort of patients. A person having ordinary skill in the art would have to perform multiple further in vivo experiments in order to validate elevated anti-PD1 AAbs indicate other forms of cancer, and perform multiple further experiment, in animal models that are predictive of treating a representative number of cancers, in order to demonstrate CPIs as a whole can be used with a reasonable expectation of success. The amount of experimentation required for enabling guidance, commensurate in scope with the breadth of the claims, goes beyond what is considered ‘routine’ within the art, and constitutes undue further experimentation.
Therefore, Claims 1, 3 and 5-15 are rejected under 35 U.S.C. 112, first paragraph, for failing to meet the enablement requirement.
Claim Rejections - 35 USC § 101 (Maintained)
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.
As currently amended, Claims 1, 3 and 5-15 stand as rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception(s) (natural law and mental process(es)) without significantly more, for reasons of record in the previous Office action.
On pages 6-7 of Remarks filed 15 September 2025, Applicant asserts, “When the additional elements are viewed as a combination, the claim elements amount to a claim as a whole that adds meaningful limits on the use of the exception. The totality of these steps including the recitation of treatment integrate any judicial exception present into the diagnostic and treatment process. See eg., ‘Subject Matter Eligibility Examples: Life Sciences,’ Example 29, claim 6 (available at: uspto.gov/sites/default/files/documents/ieg-may-2016-ex.pdf). Further, the combination of steps, ensures that critically ill patients will be accurately diagnosed and properly treated, as opposed to lacking accurate monitoring of the treatment. See Diamond v. Diehr, 450 U.S. 175, 188 (1981) (“a new combination of steps in a process may be patentable even though all the constituents of the combination were well known and in common use before the combination was made’). Thus, the claim elements, when considered as a combination with the other additional elements, yield a claim as a whole that amounts to significantly more than the exception itself.”
This is not persuasive because the claims are contingent claims and MPEP 2111.04 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. For example, assume a method claim requires step A if a first condition happens and step B if a second condition happens. If the claimed invention may be practiced without either the first or second condition happening, then neither step A or B is required by the broadest reasonable interpretation of the claim. If the claimed invention requires the first condition to occur, then the broadest reasonable interpretation of the claim requires step A. If the claimed invention requires both the first and second conditions to occur, then the broadest reasonable interpretation of the claim requires both steps A and B.” Thus, the broadest reasonable interpretation (BRI) of the method only requires “determining a level of an anti-PD1 autoantibody in a blood sample from the subject”. Since step (b) comprising administering is contingent upon “if the level of the anti-PD1 autoantibody is determined to be elevated relative to a control level” then it is not part of the BRI. Additionally, MPEP 2106.04(d)(2) regarding the Particular Treatment integration consideration under 101 analysis, states: “in order to qualify as a ‘treatment’ or ‘prophylaxis’ limitation for purposes of this consideration, the claim limitation in question must affirmatively recite an action that effects a particular treatment or prophylaxis for a disease or medical condition.” The instant claims do not affirmatively require treatment, the method may be practiced and anticipated solely by determining a level of an anti-PD1 autoantibody in a blood sample from the subject. The Examiner has provided evidence of record that it was well established in the field of technical expertise that autoantibodies against PD1 were detected in serum samples from human patients by ELISA (Shi et al. 2017, art of record). The data revealed increased levels of anti-PD-1 IgG, but not IgM are found in new-onset SLE patients (Abstract Results). Therefore, the additional elements were all well understood, routine, conventional activities prior to filing the application at hand and, thus, the ordered combination of elements/steps do not provide significantly more than what was known in the art before the effective filing date of the application.
For all of these reasons, Claims 1, 3 and 5-15 are directed to the judicial exception without significantly more and stand as rejected under 35 U.S.C. 101.
It should be noted, however, that this rejection may be obviated by limiting the scope of the claimed invention to the enabled scope indicated in the rejection above. For example, limiting the method of the invention to the identification of subjects having HNSCC comprising detecting elevated anti-PD1 autoantibodies in a blood sample relative to levels in healthy controls, and treating comprising administering atezolizumab would provide integration of the judicial exception into a particular treatment and/or add a level of specificity to the claimed invention that amounts to significantly more than the judicial exception itself.
Claim Rejections - 35 USC § 102 (Maintained)
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.
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.
As currently amended, Claims 1, 3 and 5-15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Shi et al., Arthritis Research & Therapy (2017) 19:52-62, as evidenced by Song et al., Arthritis Research & Therapy (2018) 20:270-283, for reasons of record in the previous Office action.
On page 7 of Remarks filed on 15 September 2025, Applicant asserts, “Neither Shi et al nor Song et al discloses the treatment of cancer patients identified as having elevated anti-PD1 autoantibody levels”. This is not persuasive because the broadest reasonable interpretation (BRI) of the method only requires “determining a level of an anti-PD1 autoantibody in a blood sample from the subject”. Since step (b) comprising administering is contingent upon “if the level of the anti-PD1 autoantibody is determined to be elevated relative to a control level” then it is not part of the BRI.
While the Shi prior art explicitly discloses increased serum levels of PD1 autoantibodies in SLE patients (pg. 4, Results, second paragraph), it does not expressly disclose an association between the elevated levels and cancer. The Song prior art reference, however, is relied upon as evidence that SLE is necessarily “associated with increased risk of overall cancers, cancer risk in both genders, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, leukemia, multiple myeloma, cervix, vagina/vulva, renal, bladder, esophagus, gastric, hepatobiliary, lung, oropharynx, larynx, non-melanoma skin, and thyroid cancers” (ABSTRACT, Results).
Therefore, the BRI of the invention fails to distinguish over methods that were disclosed in the art prior to filing, and the rejection is maintained.
Conclusion
No claim is allowed.
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/STACEY N MACFARLANE/Examiner, Art Unit 1675