DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
1. The response filed on 2/23/2026 to the restriction requirement of 11/25/2025 has been received. Applicant has elected for examination Group I. Because Applicant did not distinctly and specifically point out any errors in the restriction requirement, the election has been treated as an election without traverse (MPEP 818.03(a)). Claims 23, 25-27, 34-36, 42, 43, 45, 48-50, 53-55, and 61-64 are pending. Claims 28, 33, and 58 have been cancelled without prejudice by Applicant. Claims 23, 25-27, 34-36, 42, 43, 45, 48-50, 53-55, and 61-64 are currently under prosecution.
Priority
2. The present application claims the priority of PCT/US2022/012371 filed on 1/13/2022, which claims the benefit of provisional application 63/138,170 filed on 1/15/2021. The subject matter of the present application has been reviewed and it was determined that claims 23, 25-27, 34-36, 45, 48-50, 53-55, and 61-64 are granted the benefit and priority of provisional application 63/138,170 and have the effective filing date of 1/15/2021. Claims 42 and 43 are granted the benefit and priority of the PCT application and have the effective filing date of 1/15/2022.
Specification
3. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Improper hyperlinks can be found in the following locations:
Page 8 [0017] lines 8 and 11; and
Page 55 [00183] line 4
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 Interpretation
4. Claim 23 contains the phrase “assaying or having assayed a level of immune content in a biological sample comprising immune cells and/or prostate cancer cells…” Applying the broadest reasonable interpretation, this phrase is reasonably interpreted to include assaying a biological sample containing immune cells, a biological sample containing prostate cancer cells, or a biological sample containing immune cells and prostate cancer cells.
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.
5. Claims 23, 25-27, 34-36, 42, 43, 45, 48-50, 53-55, 61-64 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature/ a natural phenomenon) without significantly more.
The claims recite a method for treating a patient for prostate cancer, the method comprising:
a) assaying or having assayed a level of immune content in a biological sample comprising immune cells and/or prostate cancer cells from the patient prior to treatment of the patient with immunotherapy;
b) determining or having determined whether or not the patient is likely to be responsive to immunotherapy based at least on the level of the immune content in the biological sample; and
c) administering immunotherapy to the patient if the patient is identified as likely to be responsive to immunotherapy, or administering a cancer treatment other than immunotherapy to the patient if the patient is not identified as likely to be responsive to immunotherapy. The claimed method has two possible outcomes: (1) identifying the patient as likely to be responsive to immunotherapy and administering immunotherapy to that patient; and (2) identifying the patient is not likely to be responsive to immunotherapy and administering a cancer treatment other than immunotherapy to that patient. Thus, the claims are directed to the judicial exception of naturally occurring immune content in a biological sample of a prostate cancer patient and a correlation to likelihood of response to immunotherapy.
In outcome (2), this judicial exception is not integrated into a practical application because the claims recite only the detection or observation of a naturally occurring phenomenon/law of nature, which is data gathering to observe the naturally occurring phenomenon/law of nature without applying the data to a practical application. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite use of routine laboratory procedures to detect and observe naturally occurring immune content. The steps of assaying immune content in biological samples are considered known, routine steps and are typically taken by those in the field to perform testing of a sample and are not elements that are sufficient to amount to significantly more than the judicial exception. For example, Davicioni WO2019/028285; Wu et al (Frontiers in Oncology, 2020, 10:517637; p. 1-15); Gannon et al (Journal of Immunological Methods, 2009; 348:9-17); Strasner et al (Frontiers in Oncology, 2015; 5:128, p. 1-10); Simnica et al (JCO Precision Oncology, November 2020, 4:1374-1385); Gevensleben et al (Clinical Cancer Research, 2016, 22:1969-1977); and Subudhi et al (Sci. Transl. Med., April 2020, 12:eaaz3577; p. 1-10) all teach and demonstrate routine methods of assaying levels of immune content in a biological sample from a prostate cancer patient, including measuring immune cell biomarkers and activity. Routine data gathering in order to observe a natural phenomenon/ natural principle does not add a meaningful limitation to the method as it would be routinely used by those of ordinary skill in the art in order to observe the natural phenomenon/ natural principle, and it fails to narrow the scope of the claims such that others are not foreclosed from using the law of nature/natural phenomenon. Methods of detecting natural phenomenon preempt all practical uses of it as others must use/detect the natural phenomenon to apply it to any other correlations, diagnosis, prognosis, therapeutic response, monitoring, etc.
In outcome (2), this judicial exception is not integrated into a practical application because the step of “administering a cancer treatment other than immunotherapy” if the patient is not identified as likely to be responsive to immunotherapy is a generic instruction to apply the judicial exception and does not amount to significantly more than the judicial exception. It is a limitation that is well-understood, routine, conventional activity in the field of treating cancer and does not amount to significantly more than the judicial exception (see MPEP 2106.05(d)). Generic treatment steps are no more than appending conventional steps specified at a high level of generality, are a generic direction to “apply it,” and fail to supply inventive concept to the judicial exception. The step of “administering a cancer treatment other than immunotherapy” does not apply or use the judicial exception to effect a particular treatment (see MPEP 2106.05(f)). The treatment step of claim 23 in outcome (2) fails to amount to an element significantly more than the judicial exception.
To obviate the rejection, there must be at least one additional element or physical step that applies, relies on, or uses the natural principle so that the claim amounts to significantly more than the judicial exception itself. The claimed method currently fails to provide a practical application of the judicial exception and fails to add any elements that amount to significantly more than the judicial exception.
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.
6. Claim 36 is 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 36 recites the limitation "the CD138/syndecan-1 level" in line 5. There is insufficient antecedent basis for this limitation in the claim. Please amend to recite “a CD138/syndecan-1 level.”
7. Claims 23, 25-27, 34-36, 42, 43, 45, 48-50, 53-55, and 61-64 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 23 recites:
a method for treating a patient for prostate cancer, the method comprising:
a) assaying or having assayed a level of immune content in a biological sample comprising immune cells and/or prostate cancer cells from the patient prior to treatment of the patient with immunotherapy;
b) determining or having determined whether or not the patient is likely to be responsive to immunotherapy based at least on the level of the immune content in the biological sample; and
c) administering immunotherapy to the patient if the patient is identified as likely to be responsive to immunotherapy, or administering a cancer treatment other than immunotherapy to the patient if the patient is not identified as likely to be responsive to immunotherapy.
Claim 34 recites: The method of claim 23 wherein a higher level of immune content compared to a control reference value indicates that the patient will likely respond to immunotherapy.
Claim 23 is unclear with regard to the basis used for determining whether or not the patient is likely to be responsive to immunotherapy. The claim recites the determination is based on the level of immune content in the biological sample. Based on the level how? The scope of patients identified as likely to be responsive or not is unclear because the basis of determination is unclear. Therefore, the scope of patients receiving immunotherapy or receiving cancer therapy that is not immunotherapy is unclear. The metes and bounds of the claimed invention cannot be determined.
Claim 34 recites that a higher level of immune content compared to a control reference value identifies a patient as likely to respond to immunotherapy, however, claim 34 does not identify what the control reference value is for comparison. The instant specification discloses that:
[0074] Control samples may include tissue and/or nucleic acids obtained from or representative of tumor samples from patients showing no evidence of disease, as well as tissue and/or nucleic acids obtained from or representative of tumor samples from patients that develop systemic cancer.
Therefore, the specification provides a non-limiting definition of “control samples” that can be derived from any of tumor samples, tumor tissues, nucleic acids, or samples from healthy individuals with no disease. However, the specification does not identify what a “control reference value” is. Claim 34 does not identify what a “control reference value” is in order for one to determine the scope of patients having immune content levels higher or lower than the “control reference value”. Therefore, the scope of patients receiving immunotherapy or receiving cancer therapy that is not immunotherapy is unclear. The metes and bounds of the claimed invention cannot be determined.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
8. Claim 45 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 45 recites “wherein the method is performed prior to treatment of the patient with immunotherapy”. Claim 23 from which claim 45 depends recites the method comprising “a) assaying or having assayed a level of immune content…prior to treatment of the patient with immunotherapy;” Therefore claim 45 fails to further limit the subject matter because claim 23 already claims the method occurs prior to treatment with immunotherapy. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
9. Claims 23, 25-27, 34, 35, 43, 48-50, and 53-54 are rejected under 35 U.S.C. 103 as being unpatentable over Davicioni (WO2019/028285, pub. 2/7/2019).
Davicioni discloses a method for treating a patient for prostate cancer, the method comprising: assaying or having assayed a level of immune content in a biological sample comprising cancer cells from the patient with cancer; determining the prognosis of the patient based on immune content in the biological sample; and administering a treatment to the patient based on what the assayed level of immune content within the biological sample. (See Davicioni, pg. 3 [0010]).
Davicioni does not disclose using the method to determine whether a prostate cancer patient will be responsive to immunotherapy.
Davicioni teaches the method could be used for determining whether to modify, recommend, continue, or discontinue anti-cancer therapy regimens including immunotherapy. (See Davicioni, pg. 32 [00139]).
In regards to claims 25-27, Davicioni teaches that immunotherapy could be cellular immunotherapy, antibody immunotherapy, or cytokine immunotherapy (See Davicioni, pg. 37 [00161]), and Sipuleucel-T is an immunotherapy agent for treating prostate cancer (See Davicioni, pg. 2 [0005]), and other therapeutic regimens for treating prostate cancer are surgery, radiation therapy, chemotherapy, hormonal therapy, and biological therapy (See Davicioni, pg. 3 [0010]).
In regard to claim 34, Davicioni discloses a higher level of immune content compared to a control reference value indicates a response to treatment. (See Davicioni, pg. 46 [00197]).
In regard to claim 35, Davicioni discloses assessing natural killer cell activity as a level of Immune content. (See Davicioni, pg. 3 [0010]).
In regard to claim 43, Davicioni discloses assaying the immune content score by assaying the expression level of any one or more of the following markers: ICOS, CTLA-4, and LAG3. (See Davicioni, pg. 47 Table 2).
In regard to claim 48, Davicioni discloses the cancer could be metastatic prostate cancer. (See Davicioni, claims 42 and 43).
In regard to claims 49, 50, 53, and 54, Davicioni discloses the sample as being a tumor or a biopsy sample (See Davicioni, pg. 7 [0024], and the method is capable of being performed before or after prostatectomy (See Davicioni, pg. 8 [0028]).
It would be prima facie obvious for a person of ordinary skill in the art prior to the effective filing date to apply the teachings of Davicioni for using the method of Davicioni to determine whether a prostate cancer patient would likely respond to immunotherapy as claimed in the present invention. The present claims present an obvious variant of the disclosure of Davicioni that could be foreseen according to the specification of Davicioni. Therefore, a person of ordinary skill in the art prior to the effective filing date could use the method of Davicioni to predict response to immunotherapy as taught in Davicioni with a reasonable expectation of success.
10. Claims 35, 36, 42, 43, 48, and 61-62 are rejected under 35 U.S.C. 103 as being unpatentable over Davicioni (WO2019/028285, pub. 2/7/2019) as applied to claims 23, 25-27, 34, 35, 43, 48-50, and 53-54 above, and further in view of Yeku (Cancer J., 2016; 22(5):334-341).
Davicioni discloses the limitations of claim 23 as described above.
Davicioni does not disclose the immune content as being increased plasma cells, tertiary lymphoid structure activity, IgG expression, or interferon gamma signaling; or the assayed levels of immune content having expressed levels of the following markers: KLK3, KLK2, FKBP5, STEAPI, STEAP2, PPAP2A, RAB3B, ACSL3, and NKX3-1; or CD27, HLA-F, HLA-B, HLA-A, B2M, HLA-E, Act CD4, Act CD8, Tem CD8, TAP2, HLA-DPB1, TAP-1, HLA-C, HLA-DPA1, MDSC, ID01, Treg, PD-L2, TIM3, PD-L1, TIGIT, and PD-1.
Yeku teaches that immunotherapy recruits the host’s immune system to recognize the tumor as foreign and reject the tumor through direct cytolytic effect. (See Yeku, pg. 1 Introduction). Yeku further teaches that immune biomarkers can be used to assess response to immunotherapies and the immune response. (See Yeku, abstract). Yeku discloses that following treatment with Sipuleucel-T, the only FDA approved immunotherapy for castrate resistant prostate cancer at the effective filing date of the application, increased expression of CD56+ NK cells, CD19+ B cells, IFN-gamma production, and IgG expression. (See Yeku, pg. 2, Mechanism of Action). Yeku also discloses the IgG expression to be directed towards prostate associated tumor antigens including KLK2 and KLK3. (See Yeku, pg. 3 paragraph 1). Yeku also discloses that radical prostatectomy samples following immunotherapy treatment expressed increased filtration of CD8+ lymphocytes, T-regulatory lymphocytes, and PD-1 expression. (See Yeku, pg. 3 paragraph 1).
It would be prima facie obvious to a person of ordinary skill in the art prior to the effective filing date to use the method of Davicioni to predict response to immunotherapy in prostate cancer patients based on the disclosed immune content of Yeku. It would have been obvious because Yeku teaches that immunotherapy recruits the host’s immune response to attack the tumor and immune expression following treatment with an immunotherapeutic agent would indicate what immune factors are being activated to target the tumor by the immune system and thereby necessary for an effective response to immunotherapy. Further, Yeku teaches that Sipuleucel-T is an approved immunotherapy treatment for prostate cancer and it increases the expression of IFN-gamma signaling and IgG expression, thereby presence of these markers prior to treatment would provide a reasonable expectation of success at predicting response to immunotherapy. Therefore, it would be obvious to a person of ordinary skill in the art to assay the disclosed immune biomarkers of Yeku to predict the response to immunotherapy in prostate cancer patient by the method of Davicioni as claimed in the present invention.
11. Claims 34-36, 43, and 63-64 are rejected under 35 U.S.C. 103 as being unpatentable over Davicioni (WO2019/028285, pub. 2/7/2019) as applied to claims 23, 25-27, 34, 35, 43, 48-50, and 53-54 above, and further in view of Jansen (Urol Oncol. 2019; 37(8):543-555).
Davicioni discloses the claim limitations of claim 23 as described above.
Davicioni does not disclose the immune content as being increased plasma cells, tertiary lymphoid structure activity, IgG expression, or interferon gamma signaling; or the assayed levels of immune content having expressed levels of the following markers: KLK3, KLK2, FKBP5, STEAPI, STEAP2, PPAP2A, RAB3B, ACSL3, and NKX3-1; or CD27, HLA-F, HLA-B, HLA-A, B2M, HLA-E, Act CD4, Act CD8, Tem CD8, TAP2, HLA-DPB1, TAP-1, HLA-C, HLA-DPA1, MDSC, ID01, Treg, PD-L2, TIM3, PD-L1, TIGIT, and PD-1.
Jansen teaches that the organization, location, and phenotype of the immune cell subsets of the tumor microenvironment are crucial to the anti-tumor immune response. (See Jansen, pg. 4, Prognostically valuable and functionally important). Jansen teaches that immune content relevant to predicting immunotherapeutic response in solid tumor cancers, including prostate, includes tertiary lymphoid structure activity and signaling within the tumor microenvironment including the presence or increase of CD8+ T cells, the absence or decreased presence of T regulatory cells, and the increase of TH1-type cells. (See Jansen pg. 10-11 Section 4.2).
It would be prima facie obvious to a person of ordinary skill in the art prior to the effective filing date to use the method of Davicioni for predicting the response of immunotherapy in prostate cancer patients based on the disclosed immune content of Jansen for the claimed invention. It would be obvious because Jansen teaches the organization of the immune cells in the tumor microenvironment are crucial for the anti-tumor immune response and the tertiary lymphoid structure organizes the lymphoid system within the tumor microenvironment. Jansen further teaches that the tertiary lymphoid structure activity is associated with favorable clinical outcomes for solid tumor cancers including prostate cancer. Specifically, Jansen teaches that tertiary lymphoid structure activity associated with increased CD8+ T cells and TH1 type cells, which are associated with increased IFN-gamma expression, could predict a response to immunotherapy with a reasonable expectation of success. Therefore, it would be obvious to a person of ordinary skill in the art prior to the effective filing date to assay the tertiary lymphoid structures of the prostate tumor microenvironment and use TLS activity and activity signaling to predict the response of immunotherapy in prostate cancer patients of the present claimed invention.
12. Claim 55 is rejected under 35 U.S.C. 103 as being unpatentable over Davicioni (WO2019/028285, pub. 2/7/2019) as applied to claims 23, 25-27, 34, 35, 43, 48-50, and 53-54 above, and further in view of Pernar (Cold Spring Harb Perspect Med 2018; 8:a030361).
Davicioni discloses the limitations of claim 23 as described above.
Davicioni does not disclose the patient is black or of African descent.
Pernar teaches the incidence and mortality rate of prostate cancer is highest in black men. (see Pernar, pg. 6 column 1, paragraph 2, also Figure 4).
It would have been prima facie obvious for a person of ordinary skill in the art prior to the effective date to use the method of Davicioni with black men based on the teaching of Pernar. It would have been obvious because if the incidence and mortality rate is highest in this population, a predictive response to therapy would be highly beneficial. Therefore, it would be obvious for a person of ordinary skill in the art to apply the teaching of Pernar to the method of Davicioni with a reasonable expectation of success prior to the effective filing date.
Conclusion
13. Claims 23, 25-27, 34-36, 42, 43, 45, 48-50, 53-55, and 61-64 are rejected.
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/LINDSAY DUNN/Examiner, Art Unit 1644
/Laura B Goddard/Primary Examiner, Art Unit 1642
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