DETAILED ACTION
Status of Application
Claims 1-3, 5, 7-9, 11-14, 16, 18-19, 21-22, 25-27, and 29 are pending
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
A preliminary amendment of claims 3, 5, 7-9, 11-14, 16, 18-19, 21-22, 25-27, and 29, and cancellation of claims 4, 6, 10, 15, 17, 20, 23-24, 28, and 30-35 as submitted in a communication filed on 07/07/2025 is acknowledged.
The species election, in the reply filed on 08/12/2026, was made without traverse for the following species:
Species Group 1: Melanoma
Species Group 2: PD-1 inhibitor
Claims 1-3, 5, 7-9, 11-14, 16, 18-19, 21-22, 25-27, and 29 are at issue and will be examined to the extent they encompass the elected invention.
Priority
Acknowledgment is made of a claim for foreign priority under 35 U.S.C. 119(a)-(d) to PCT/EP2022/061485 filed on 04/29/2022. Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d), which papers have been placed of record in the file.
This is the US national application which entered the national stage from
Application No. PCT/EP2023/061307 filed on 04/28/2023.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12/19/2024, 02/18/2025, 12/19/2025, and 05/12/2026 are acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
The drawings submitted on 10/23/2024 have been reviewed and are accepted by
the examiner for examination purposes.
Specification Objections
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on page 6. 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.
Claims Objections
Claim 1 is objected to due to the recitation of “…after first treatment with the one or more immune checkpoint inhibitors…”. It should be amended to recite “…after the first treatment with the one or more immune checkpoint inhibitors…”. Appropriate correction is required.
Claim 5 is objected to due to the recitation of “The method of claim 3 the patient…”. It should be amended to recite “The method of claim 3 wherein the patient…”. Appropriate correction is required.
Claim 16 is objected to due to depending on a cancelled claim. Appropriate correction is required.
Claim 25 is objected due to the recitation of “ICI”. Abbreviations, unless otherwise obvious and/or commonly used in the art, should not be recited in the claims without at least once reciting the entire phrase for which the abbreviation is used. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA )
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 1-3, 5, 7-9, 11-14, 16, 18-19, 21-22, 25-27, and 29 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.
Claims 1, 13, 14, 16, and 18 (claims 3, 5, 7-9, 11-12, 21-22, 25-27, and 29 dependent thereon) is indefinite due to the term “sample”, for the following reason: It is unclear what constitutes as a sample in this case. For examination purposes, we will interpret “sample” as any possible sample. Correction is required.
Claims 2-3, 5, 7-9, 11, and 19 (claims 12-14, 21, 25-27, and 29 dependent thereon) is indefinite for the terms “stratifying” and “stratified”, for the following reason: It is unclear how the individuals are being stratified in this case. Correction is required.
Claims 7, 8, 9, 11, 19, and 25 is indefinite in the recitation of “a cut off value”, for the following reason: The cut off value is not defined. Therefore, it is unclear what the cut off value is required for the claimed method in this case. Correction is required.
Claim 13 is indefinite due to the term “successful treatment”, for the following reason: The term “successful treatment” is vague, as is unclear what treatment would be considered successful in this case. Correction is required.
Claim 16 is indefinite due to the term “unsuccessful treatment”, for the following reason: The term “unsuccessful treatment” is vague, as is unclear what treatment would be considered unsuccessful in this case. Furthermore, claim 16 is rejected as incomplete due to depending on canceled claim 15. Correction is required.
Claim 18 (claim 19 dependent thereon) is indefinite in the recitation of “g)”, for the following reason: Claim 18 ultimately depends on claim 1 via claim 3. Claims 1 and 3 do not recite steps “e)” or “f)”. Therefore, it is unclear what all the steps before “g)” would be in this case. Correction is required.
Claim 21 is indefinite in the recitation of “(h)”, for the following reason: Claim 18 ultimately depends on claim 1 via claim 3. Claims 1 and 3 do not recite steps “e)”, “f)”, or “g)”. Therefore, it is unclear what all the steps before “h)” would be in this case. Correction is required.
Claim Rejections - 35 USC § 112(a) or First Paragraph (pre-AIA )
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.
Claims 1-3, 5, 7-9, 11-14, 16, 18-19, 21-22, 25-27, and 29 are 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
As stated in MPEP 2111.01, during examination, the claims must be interpreted as broadly as their terms reasonably allow.
Claims 1-3, 5, 7-9, 11-14, 16, 18-22, 25-27, and 29 are directed in part to a method for determining the prognosis of an individual having any cancer and being considered for treatment with, or currently being treated with, one or more of any immune checkpoint inhibitors. See claim rejections under 35 usc 112(b) for claim interpretation.
This specification discloses the claimed method with respect to melanoma, breast cancer, and ovarian cancer, and immune checkpoint inhibitors including CTLA-4 and PD-1 inhibitors. However, the claims encompass the method for any cancer and any immune checkpoint inhibitor. The specification does not disclose a representative number of species commensurate with this scope of identifying characteristics demonstrating possession of the broader genus.
While one could argue that the method disclosed can be used on any cancer or any immune checkpoint inhibitors, it is noted that art teaches examples of how immune checkpoint inhibitors do not work on all cancer types. For example, Teber et al. (lombardi.georgetown.edu, Study Shows Why a Common Form of Immunotherapy Fails, and Suggests Solution published 08/02/2019) teach that up to 85 percent of patients whose cancer is treated with checkpoint inhibitors don't benefit from the treatment (Paragraph 2). Therefore, one cannot reasonably conclude that the method disclosed, including determining the prognosis of an individual having melanoma, breast, or ovarian cancer and being considered for treatment with, or currently being treated with, one or more immune checkpoint inhibitors selected from a CTLA-4 inhibitor and PD-1 inhibitor, is representative of the method that is required by the claimed process. Thus, one of ordinary skill in the art would not recognize from the disclosure that Applicant was in possession of the claimed invention.
Claims 1-3, 5, 7-9, 11-14, 16, 18-19, 21-22, 25-27, and 29 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 for determining the prognosis of an individual having melanoma, breast, or ovarian cancer and being considered for treatment with, or currently being treated with, one or more immune checkpoint inhibitors selected from a CTLA-4 inhibitor and PD-1 inhibitor, it does not enable a method for determining the prognosis of an individual having any cancer and being considered for treatment with, or currently being treated with, one or more of any immune checkpoint inhibitor. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 737, 8 USPQ2nd 1400 (Fed. Cir. 1988)) as follows: 1) quantity of experimentation necessary, 2) the amount of direction or guidance presented, 3) the presence and absence of working examples, 4) the nature of the invention, 5) the state of prior art, 6) the relative skill of those in the art, 7) the predictability or unpredictability of the art, and 8) the breadth of the claims. The factors which have led the Examiner to conclude that the specification fails to teach how to make and/or use the claimed invention without undue experimentation, are addressed in detail below.
The breadth of the claims. Claims 1-3, 5, 7-9, 11-14, 16, 18-19, 21-22, 25-27, and 29 broadly encompass a method for determining the prognosis of an individual having any cancer and being considered for treatment with, or currently being treated with, one or more of any immune checkpoint inhibitor. The enablement provided is not commensurate in scope with the claims due to the lack of knowledge regarding the elements required in the required method to include any cancer or any immune checkpoint inhibitors. In the instant case, the specification enables a method for determining the prognosis of an individual having melanoma, breast, or ovarian cancer and being considered for treatment with, or currently being treated with, one or more immune checkpoint inhibitors selected from a CTLA-4 inhibitor and PD-1 inhibitor.
The amount of direction or guidance presented and the existence of working examples. The specification discloses a method for determining the prognosis of an individual having melanoma, breast, or ovarian cancer and being considered for treatment with, or currently being treated with, one or more immune checkpoint inhibitors selected from a CTLA-4 inhibitor and PD-1 inhibitor. However, the specification fails to provide any clue as to the elements required in method for determining the prognosis of an individual having any cancer and being considered for treatment with, or currently being treated with, one or more of any immune checkpoint inhibitors. No guidance has been presented to lead one of ordinary skill to arrive to a method for determining the prognosis of an individual having any cancer and being considered for treatment with, or currently being treated with, one or more of any immune checkpoint inhibitors.
The state of prior art, the relative skill of those in the art, and the predictability or unpredictability of the art. The type of cancer determines treatment. While the art discloses a limited number of cancers and immune checkpoint inhibitors, neither the specification nor the art provide a correlation between cancer types and immune checkpoint inhibitors such that one of skill in the art can envision all the cancers that can be treated by any immune checkpoint inhibitor. The art clearly teaches that immune checkpoint inhibitors do not work on all cancer types. For example, Teber et al. (lombardi.georgetown.edu, Study Shows Why a Common Form of Immunotherapy Fails, and Suggests Solution published 08/02/2019) teach that up to 85 percent of patients whose cancer is treated with checkpoint inhibitors don't benefit from the treatment (Paragraph 2).
The quantity of experimentation required to practice the claimed invention based on the teachings of the specification. While methods of determining which cancers can be treated with immune checkpoint inhibitors were known in the art at the time of the invention, it was not routine in the art to screen by a trial and error process for an essentially infinite number of cancers and immune checkpoint inhibitors to arrive to the claimed method.
Therefore, taking into consideration the extremely broad scope of the claim, the lack of guidance, the amount of information provided, and the high degree of unpredictability in the prior art, one of ordinary skill in the art would have to go through the burden of undue experimentation in order to practice the claimed invention. Thus, Applicant has not provided sufficient guidance to enable one of ordinary skill in the art to make and use the invention in a manner reasonably correlated with the scope of the claims.
Claim Rejections - 35 USC § 103 (AIA )
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status
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.
Claims 1-3, 7-8, 18-19, 21-22, 26-27, 29 are rejected under 35 U.S.C. 103 as being unpatentable over Svedman et al. (Cited in IDS 12/19/2024; hereby “Svedman”).
Svedman teaches Immune checkpoint inhibitors (ICI) are effective in fractions of patients with disseminated melanoma (summary). Svedman teaches that plasma samples were collected from patients with unresectable metastatic cutaneous melanoma, treated with ICI (anti-CTLA-4 and/oranti-PD-1) (Page 2; 2.1. Patients and Plasma Samples). Svedman teaches that blood samples were taken from the patients within 5 days prior to treatment started (Page 2; 2.1. Patients and Plasma Samples). Svedman teaches that the treatments were administrated according to standard ICI regimens and dosage approved for the treatment of metastatic melanoma (Page 2; 2.1. Patients and Plasma Samples). Svedman teaches that routine follow-up after initiating the ICI treatment included monthly clinical assessments (Page 3; 2.3. Follow-up).
Svedman teaches that high pretreatment plasma TKa levels were significantly associated with worse baseline characteristics and poor response and survival in ICI-treated melanoma patients (Page 10, 5. Conclusion). Svedman teaches that circulating levels of TKa, measured with the DiviTum assay, have been shown to be associated with disease stage, prognosis, and treatment efficacy in several cancer types, including breast, lung, pancreatic, and renal cell cancer (Page 2; second paragraph of introduction). Svedman teaches that the median TKa at baseline gave a cut-off that divided patients with very similar TKa levels into different groups (Page 4; 3.2 Determining the cut-off for Tka). Svedman teaches that characteristics of melanoma patients with low (<60Du/L) or high thymidine kinase1(TK) activity (Du/L) in plasma before starting immune checkpoint inhibitor treatment (Table 2). Plasma TK activity (TKa) levels were determined using the DiviTum TKa ELISA assay; TKa levels were correlated with patients’ baseline characteristics, response rate (RR), progression-free survival (PFS), and overall survival (OS) (Abstract). Plasma samples were collected prior to treatment start in patients with unresectable metastatic cutaneous melanoma, treated with an anti-PD-1 inhibitor (Abstract). Svedman teaches that high pretreatment plasma TKa levels were significantly associated with worse baseline characteristics and poor response and survival in ICI-treated melanoma patients (Abstract). Svedman discloses the determination the cut-off for thymidine kinase 1 activity (TKa) in the plasma of metastatic melanoma patients treated with immune checkpoint wherein the median gave a cut-off that divided patients with very similar TKa values into different groups (Figure 1). Svedman teaches high Tka levels were associated with elevated LDH and a higher median LDH (Page 5; 3.3 Charactericss and outcomes of patients with high or low Tka). Svedman teaches that the Tka low group had LDH levels that ranged form 1.7-14.2 mikrokat/L (Table 2)
Svedman does not teach obtaining TKa measurements after the start of treatment. Svedman does not teach further treatment with one or more immune checkpoint inhibitors or an alternative cancer therapy based on the outcome.
However, Svedman teaches further analyses of the effects of TKa dynamics after treatment start will be valuable (Page 10; last paragraph of Discussion).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to obtain Tka measurements after initiation of treatment and based off the result of Tka measurements after treatment, to continue treatment with the immune checkpoint inhibitors or administer an alternative cancer treatment. A person of ordinary skill in the art is motivated to obtain Tka measurements after initiation of treatment to determine continuing treatment because Svedmen teaches that Tka levels are associated with treatment response and survival. Furthermore, Svedmen teaches that Tka dynamics after the start of treatment would be valuable information. Accordingly, one of ordinary skill would have been motivated to monitor Tka after treatment initiation to assess treatment response and guide subsequent treatment decisions. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claims 5, 9, 11, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Svedman et al. (Cited in IDS 12/19/2024; hereby “Svedman”), as applied to claims 1-3, 7-8, 18-19, 21-22, 26-27, 29, in view of Wang et al. (Analytical Cellular Pathology 23.1 (2001): 11-19; hereby “Wang”) and Huang et al. (Nature 545.7652 (2017): 60-65; hereby “Huang”),
The teachings of Svedman are discussed above.
Svedman does not teach an increased TKa after the administration of immune checkpoint inhibitors.
Huang enrolled 29 patients with stage IV melanoma treated with the anti-PD-1 antibody pembrolizumab (pembro) (Page 60, right column, first full paragraph). Huang teaches that the frequency of Ki67+ CD8 T cells increased in 3 weeks after pembro treatment and then declined in most patients (Fig. 1b).
Wang teaches that cell proliferation increases thymidine kinase due to its involvement in DNA replication (abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to expect an increased Tka level after administration of an immune checkpoint inhibitor. A person of ordinary skill in the art is motivated to expect an increased Tka level because Huang teaches an increase in cellular proliferation after immune checkpoint inhibitor and Wang teaches that cellular proliferation increases thymidine kinase due to DNA replication. Thus, one of ordinary skill would reasonably expect an increase in TKa after the administration of immune checkpoint inhibitors. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claims 13-14, 16 are rejected under 35 U.S.C. 103 as being unpatentable over Svedman et al. (Cited in IDS 12/19/2024; hereby “Svedman”), in view of Wang et al. (Analytical Cellular Pathology 23.1 (2001): 11-19; hereby “Wang”) and Huang et al. (Nature 545.7652 (2017): 60-65; hereby “Huang”), as applied to claims 1-3, 5, 7-9, 11, 18-22, 25-27, 29 above, in further view of Malay et al. (Plastic and reconstructive surgery 130.4 (2012): 959)
The combined teachings of Svedman, Wang, and Huang are discussed above
The combined teachings of Svedman, Wang, and Huang do not teach the use of control samples.
Malay teaches that a control group discriminates outcomes caused by the treatment or intervention of interest from those caused by other factors, such as natural course of disease, patient or observer expectations, or other treatments (Page 959; left column). Malay teaches that the use of control groups in clinical research is essential for testing the validity of a treatment’s effect (Page 964; Conclusions).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include control samples when determining the prognostic effect of the immune checkpoint inhibitor. A person of ordinary skill in the art is motivated to use control samples because Malay teaches the benefits of control samples in clinical research. Accordingly, the use of the control samples would be beneficial to distinguish outcomes attributable to the immune checkpoint inhibitors from outcomes attributable to other factors and access the validity of the treatment. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
No claim is in condition for allowance.
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/S.L.S./Examiner, Art Unit 1652
/ROBERT B MONDESI/Supervisory Patent Examiner, Art Unit 1652
