Office Action 1: Non-Final Rejection (2023-12-19)
Rejection types: 101 - Patent-Eligible Subject Matter, 103 - Obviousness, 112 - Written Description/Enablement

CLAIMS:
First Named Inventor Thomas S. Kupper Attorney Docket No.: 29618-0294002 / BWH 25574 AMENDMENTS TO THE CLAIMS ListinM of Claims (replacin\- prior versions):

1\. (Original) A method of treating a subject who has primary melanoma, the method comprising:
obtaining a biopsy sample from the primary melanoma;
determining the T cell frequency (TCFr) of said sample; and
treating said subject with an aggressive treatment when the TCFr is greater than a reference level.

2\. (Original) A method of selecting a subject with primary melanoma for aggressive treatment, the method comprising:
obtaining a biopsy sample from the primary melanoma;
determining the T cell frequency (TCFr) of said sample; and
selecting a subject who has a TCFr below a reference level for aggressive treatment.

3\. (Original) A method of predicting whether a subject with primary melanoma is likely to progress to metastatic melanoma, the method comprising:
obtaining a biopsy sample from the primary melanoma;
determining the T cell frequency (TCFr) of said sample; and
identifying a subject who has a TCFr below a reference level as likely to progress to metastatic melanoma.

4\. (Currently Amended) The method of claim 1, wherein the primary melanoma is cutaneous melanoma.

5\. (Original) The method of claim 4, wherein the primary melanoma is 1-4 mm thick.

6\. (Original) The method of claim 5, wherein the primary melanoma is stage I to IIC.
7\. (Currently Amended) The method of claim 1, wherein determining the T cell frequency (TCFr) of said skin sample comprises analyzing T-cell receptor beta (TCR R) gene First Named Inventor Thomas S. Kupper Attorney Docket No.: 29618-0294002 / BWH 25574 sequences in substantially every T cell in the sample, quantitating total nucleated cells and calculating the proportion of T cells in the sample relative to its total number of nucleated cells.

8\. (Original) The method of claim 7, wherein said analyzing is performed by high-throughput DNA sequencing.

9\. (Currently Amended) The method of claim 1, wherein the aggressive treatment is targeted treatment, immunotherapy, chemotherapy, and/or radiation, or a combination thereof.

10\. (Original) The method of claim 9, wherein the chemotherapy comprises administration of one or more nitrosoureas; alkylating agents; microtubule targeting agents; or platinum- containing agents.

11\. (Original) The method of claim 9, wherein the targeted treatment comprises a BRAF inhibitor and/or a MEK inhibitor.

12\. (Original) The method of claim 9, wherein the immunotherapy comprises administration of a checkpoint inhibitor.

13\. (Original) The method of claim 9, wherein the immunotherapy comprises administration of a vaccines targeting melanoma cells, peptide-based vaccine, viral vector-based vaccine, or
dendritic cell vaccine.

14\. (Currently Amended) The method of claim 1, wherein the reference level is 20%.

15\. (Currently Amended) The method of claim 1, further comprising determining one or more of Breslow thickness; ulceration status; levels of mitoses/mm2; and nodal disease in the sample, and determining prognosis or selecting therapy based on TCFr and Breslow thickness; ulceration status; levels of mitoses/mm2; and/or nodal disease in the sample.

OFFICE ACTION:
DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This application is a continuation of US application no. 16/838,926, filed 04/02/2020 (now abandoned), claiming priority to provisional application 62/828,064, filed 04/02/2019.
Claim Rejections - 35 USC § 112(b)/second paragraph
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 1-2, 4-8, and 14-15 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 1-2, 4-8, and 14-15 are indefinite over the references in the claims to “aggressive treatment”.  This is a relative term that would be expected to have different meanings in different contexts; further, the term is not defined in the specification (only examples are provided), and does not have a fixed meaning in the art.  Accordingly, the term “aggressive treatment” does not have fixed boundaries, and its use in the claims renders them vague and indefinite.  It is noted that dependent claims 9-13 are excluded from this rejection because those claims are further limiting to particular, recited types of treatment (which correspond to preferred treatments taught in the disclosure).
Regarding claims 7-8, claim 7 recites the limitation said skin sample in lines 1-2.  There is insufficient antecedent basis for this limitation in the claim because claim 1, from which claim 7 depends, does not reference a “skin sample”.
Claim Rejections - 35 USC § 112(d)/fourth paragraph
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.
Claim 15 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 15 recites “determining prognosis or selecting therapy based on TCFr and” one or more other factors; however, independent claim  1, from which the claim depends, recite “treating said subject with an aggressive treatment when the TCFr is greater than a reference level” (i.e., a particular criterion that is to be met for “treating said subject with an aggressive treatment”).  While claim 1 is indefinite, claim 15 appears broader in at least some respects as compared to claim 1 – specifically, claim 15 simply recites “determining prognosis or selecting therapy based on TCFr” and one or more other factors – and thus claim 15 does not properly depend from claim 1.  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
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 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 1-15 are rejected under 35 U.S.C. 103 as being unpatentable over Tarhini et al (Journal for ImmunoTherapy of Cancer 6:112 [Oct 2018]; cited in IDS).
Initially, it is noted that no limiting definition is provided for the term “reference level”, such that the claims broadly encompass comparisons with any type of level employed as a reference in some manner.
Tarhini et al disclose the treatment of melanoma patients with ipilimumab, a checkpoint inhibitor that targets CTLA-4 (see entire reference, noting the teaching of CTLA-4 blockade by Tarhini et al page 5/10, right column); the teaching of ipilimumab administration constitutes treating with a type of immunotherapy, and based on applicant’s disclosure (and dependent claims 9 and 12), meets the requirement of an “aggressive treatment” of a subject (see, e.g., the specification at pages 24-25).
Tarhini et al further teach determining T cell frequency (TCFr) in samples, including primary melanoma samples from primary tumor biopsies (when available), as well as pre- and post-treatment metastatic tumor biopsies (see entire reference, particularly page 2/10, right column and page 3/10, both columns).  Tarhini et al report that patients exhibiting pathologic complete response (pCR) to ipilimumab were found to have significantly higher TCFr in their primary melanoma tumors, and that higher tumor T-cell clonality in primary tumor was also significantly associated with improved relapse-free survival (see Abstract, the section “Immune correlates” at page 5/10, Figures 2-3, and the Discussion at page 7).  It is noted that Tarhini et al also illustrate TCFr levels in primary melanoma tumors from patients exhibiting pCR as compared to those having residual disease, providing reference levels for both types of populations (see Figure 2).
In view of Tarhini et al’s own teachings, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have employed the method steps of Tarhini et al (of obtaining biopsy samples of a primary melanoma and determining TCFr therein) on patients having primary melanoma, and so as to have treated (as in independent claim 1) or selected for treatment (as in independent claim 2) with ipilimumab those patients whose T cell frequencies are consistent with response to ipilimumab based on the reported findings of Tarhini et al (using whatever reference level is convenient as a point of comparison, so long as it is consistent with the results reported for Tarhini et al as in their Figure 2).  As Tarhini et al report significant associations between TCFr levels in primary melanoma biopsies and ipilimumab response, an ordinary artisan would have been motivated to have performed such a method for the benefit of more appropriately treating a melanoma patient, so as to improve the likelihood of more successful treatment.  Further, regarding independent claim 3 it also would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have employed the method steps of Tarhini et al (of obtaining biopsy samples of a primary melanoma and determining TCFr therein) on patients having primary melanoma, and so as to have identified a subject as likely to progress to metastatic melanoma based on the reported findings of Tarhini et al (using whatever reference level is convenient as a point of comparison, so long as it is consistent with the results reported for Tarhini et al as in their Figure 2).  An ordinary artisan would have been motivated to have performed such a method for the benefit of more precisely determining a prognosis for a subject, allowing for more successful targeted treatment of the subject.
With further regard to dependent claims 4-6, it is noted that Tarhini et al disclose patients as specified in the claims; see, e.g., the disclosure of patients with cutaneous melanoma, and T1-4 melanoma; page 2/10, right column.  Regarding claims 7-8, the indefiniteness of these claims is again noted; Tarhini et al teach the use of TCRbeta gene sequencing, and specifically high-throughput sequencing, to determine TCFr of primary melanoma biopsy samples, which meets the requirements of these claims (see page 3/10, right column, “T-cell receptor sequencing”).  Regarding claims 9 and 12, it is reiterated that ipilimumab meets the requirements of these claims.  Regarding claims 10-11 and 13, it is noted that these claims as written do not require the actual use of the specified therapies, and claim 9 (from which these claims depend) only requires one type of “aggressive treatment” (thus, the requirements of the claims are met with regard to the alternative of immunotherapy, as addressed above).  However, it is also noted that (relevant to claims 10-11) Tarhini et al do teach the use of both chemotherapy and BRAF inhibitors in melanoma treatment; see page 6, right column-page 7 [both columns]), such that these alternatives are also obvious over the teachings of Tarhini et al.  Regarding claim 14, it is reiterated that as the claims are non-limiting with regard to a type of “reference level”, any level reasonably suggested by Tarhini et al is sufficient to meet the claims; Figure 2 of Tarhini et al also appears to illustrate a cut-off between responding and non-responding patients of approximately 20% for T cell fraction.  Regarding claim 15, this claim is also indefinite, but it is noted that Tarhini et al at least disclose Breslow thickness (page 2/10, right column).
Tarhini et al thus suggest the methods of each of claims 1-15.
Claim(s) 13 is rejected under 35 U.S.C. 103 as being unpatentable over Tarhini et al as applied to claims 1-15, above, and further in view of Wang et al (US 2016/0354409 A1 [8 Dec 2016]; cited in IDS).
This rejection applies to claim 13 to the extent that the claim further requires use of an immunotherapy that comprises administration of a peptide-based and/or viral vector-based vaccine.
The teachings of Tarhini et al are set forth above.  While Tarhini et al suggests methods meeting all of the requirements of claim 13, Tarhini et al does not teach administration of a peptide-based or viral-vector based vaccine.  Wang et al discloses use of a peptide based vaccine and viral vector-based vaccine in treating cancers, including melanoma (see the entire reference, particularly the Abstract, paragraph 44, 145, 214, Examples 2 and 16, e.g., claims 18-26).  In view of the teachings of Wang et al, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modified the methods of Tarhini et al so as to have employed a peptide-based and/or viral vector-based vaccine, as taught by Wang et al, in treatment of melanoma.  An ordinary artisan would have been motivated to have added such a therapy, or such an administering step, as an alternative possible therapy for melanoma, particularly in instances when other therapies have failed to successfully treat a patient (simple for the benefit of potentially treating the disease in such a patient).
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-15 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
With regard to claim 1 and its dependent claims, while the claimed method includes a preamble of “treating a subject who has primary melanoma”, the final step of the claim states “treating said subject....when the TCFr is greater than a reference level”, such that the claim explicitly does not require a treatment in all cases (rather, the claim clearly includes a conditional limitation, where at least some patients would not receive treatment).  As such, this claim recites and encompasses something that could be performed entirely in the human mind, i.e., deciding to not provide treatment based on test results, which is an abstract idea
Independent claims 2-3 also recite abstract ideas, claim 2 of “selecting a subject” for treatment, and claim 3 of “identifying a subject....as likely to progress to metastatic melanoma”; both of these activities could also be performed entirely in the human mind.
These judicial exceptions are not integrated into a practical application because the only active steps of the claims are data gathering steps that amount to insignificant extra-solution activity.  The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because these data gathering steps, whether considered individually or in combination, were well-understood, routine and conventional at the time of applicant’s invention (as evidenced by the teachings of Tarhini et al discussed above); the inclusion of these steps in the claims thus does not add anything significantly more than a judicial exception.
With further regard to claims 4-6, these steps are further limiting only of data gathering steps, and were known in the art at the time of the invention, and thus do not integrate the JE into a practical application, or add something significantly more than a JE.  The activities of claims 7-8 similarly are a more particular type of data gathering known in the art, as evidenced by Tarhini et al; the same analysis above that applies to claim 1 applies to these claims; this is also the case with claim 15 (particularly in view of the fact that this claim is not further limiting of claim 1).  Regarding claims 9-13, it is noted that the claims do not require any active treating that is an implementation of a JE, as discussed above.  Regarding claim 14, no particular reference level is required by the claims, and this claim requires only a more particular type of thought, which does not integrate the JE into a practical application, or add something more than a JE.  Accordingly, none of claims 1-15 is directed to patent eligible subject matter.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Inoue et al (OncoImmunology 5:9, e1204507 [April 2016]; cited in IDS) report performing TCRbeta repertoire analysis with respect to metastatic melanoma (see entire reference).  Church et al (Immunity 43:631 [Oct 2015]; cited in IDS) provide an overview of how tumor microenvironment relates to therapy response, including a discussion of the presence of infiltrating T cells (see entire reference, particularly page 632, middle and right columns).  Bethune et al (Current Opinion in Biotechnology 48:142 [May 2017]; cited in IDS) provide an overview of T cell-mediated cancer immunotherapy, suggesting a need for the more routine use of TCR repertoire sequencing (see entire reference).

APPLICANT REBUTTAL: REMARKS Status of the Claims Claims 1-15 were examined and stand rejected. Claim 1 is presently amended to incorporate the subject-matter of previous claims 4, 6, 7, 9, and 14. Claims 5, 8, and 10-13 are presently amended to update claim dependency and claim 15 is amended for clarity. Claims 2-4, 6, 7, 9, and 14 are presently cancelled without prejudice or disclaimer. These amendments are fully supported by the original claims and the specification as originally filed, e.g., at lines 25-28 on page 2; and lines 8-17 and 28 on page 3. No new matter has been added by these amendments. Upon entry of the present amendments, claims 1, 5, 8, 10-13, and 15 will be pending in this application. Reexamination and reconsideration of the claims are respectfully requested in view of these amendments and the following remarks. Claim Rejections - 35 U.S.C. & 112(b) Rejection of Claims 1, 2, 4-8, 14, and 15 Claims 1, 2, 4-8, 14, and 15 were rejected under 35 U.S.C. § 112(b) as allegedly indefinite over the reference in the claims to the term "aggressive treatment". In particular, the Office alleged (Office Action at pages 2-3): [T]he term "aggressive treatment" does not have fixed boundaries, and its use in the claims renders them vague and indefinite. It is noted that dependent claims 9-13 are excluded from this rejection because those claims are further limiting to particular, recited types of treatment (which correspond to preferred treatments taught in the disclosure). Applicant respectfully disagrees. Nonetheless, without acquiescing to the rejection and solely in furtherance of prosecution, Applicant has amended independent claim 1 to include the subject matter of previous claim 9, which, as acknowledged by the Office, is "further limiting to particular, recited types of treatment (which correspond to preferred treatments taught in the disclosure)". Claim 1, as presently amended, specifies that "the aggressive treatment is targeted treatment, immunotherapy, chemotherapy, and/or radiation, or a combination thereof', thus providing "fixed boundaries" to the term "aggressive treatment". Claims 2, 4, 6, 7, and 14 are presently cancelled, rendering all rejections directed to these claims moot. Reconsideration and withdrawal of the rejection of claim 1 and claims dependent therefrom (e.g., claims 5, 8, and 15) under 35 U.S.C. § 112(b) is kindly requested in view of the foregoing amendments and remarks. Rejection of Claims 7 and 8 Claims 7 and 8 were rejected under 35 U.S.C. § 112(b) as allegedly indefinite over recitation of the limitation "said skin sample". In particular, the Office alleged (Office Action at page 3): claim 7 recites the limitation "said skin sample" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim because claim 1, from which claim 7 depends, does not reference a "skin sample". As indicated above under "Status of the Claims", claim 7 is presently cancelled, thus rendering rejections directed to this claim moot. Insofar as the subject matter of claim 7 has been incorporated into claim 1, the limitation "said skin sample" has been removed. Claim 8 (previously depending from claim 7, and presently depending from claim 1) does not recite this limitation. Reconsideration and withdrawal of this rejection is respectfully requested in view of the foregoing. Claim Rejections - 35 U.S.C. & 112(d) Claim 15 was rejected under 35 U.S.C. § 112(d) as allegedly 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. In particular, the Office alleged (Office Action at pages 3-4): Claim 15 recites "determining prognosis or selecting therapy based on TCFr and" one or more other factors; however, independent claim 1, from which the claim depends, recite "treating said subject with an aggressive treatment when the TCFr is greater than a reference level" (i.e., a particular criterion that is to be met for "treating said subject with an aggressive treatment"). While claim 1 is indefinite, claim 15 appears broader in at least some respects as compared to claim 1 - specifically, claim 15 simply recites "determining prognosis or selecting therapy based on TCFr" and one or more other factors - and thus claim 15 does not properly depend from claim 1. Applicant respectfully disagrees. Nonetheless, without acquiescing to the rejection and solely in furtherance of prosecution, Applicant has amended claim 15 to recite: 15. The method of claim 1, further comprising determining one or more of Breslow thickness, ulceration status, levels of mitoses/mm2, and nodal disease in the sample; and treating a subject with the aggressive treatment when the one or more of Breslow thickness, ulceration status; levels of mitoses/mm2, and nodal disease is high in the sample. Thus, present claim 15 does not "simply recite "determining prognosis or selecting therapy based on TCFr"" - as alleged by the Office. Rather, claim 15 recites a method that limits the method of claim 1 by further determining one or more of Breslow thickness, ulceration status, levels of mitoses/mm2, and nodal disease in the sample, and then treating a subject with the aggressive treatment when one or more of these parameters is high in the sample. Thus, at least as presently amended, claim 15 includes all the limitations of claim 1 and further limits the subject matter of claim 1, from which it depends. Reconsideration and withdrawal of the rejection of claim 15 under 35 U.S.C. § 112(d) is kindly requested in view of the foregoing amendments and remarks. Claim Rejections - 35 U.S.C. & 103 Rejection over Tarhini Claims 1-15 were rejected under 35 U.S.C. § 103 as allegedly obvious over Tarhini et al. (Journal for ImmunoTherapy of Cancer 6:112 [Oct 2018]; "Tarhini"). In particular, the Office alleged (Office Action at pages 4-5): Initially, it is noted that no limiting definition is provided for the term "reference level", such that the claims broadly encompass comparisons with any type of level employed as a reference in some manner... In view of Tarhini et al's own teachings, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have employed the method steps of Tarhini et al (of obtaining biopsy samples of a primary melanoma and determining TCFr therein) on patients having primary melanoma, and so as to have treated (as in independent claim 1) or selected for treatment (as in independent claim 2) with ipilimumab those patients whose T cell frequencies are consistent with response to ipilimumab based on the reported findings of Tarhini et al (using whatever reference level is convenient as a point of comparison, so long as it is consistent with the results reported for Tarhini et al as in their Figure 2). Claims 2-4, 6, 7, 9, and 14 are presently cancelled, rendering all rejections directed to these claims moot. Applicant respectfully traverses the rejection as applied to present claim 1 and claims dependent therefrom (i.e., claims 5, 8, 10-13, and 15). To establish aprimafacie case of obviousness, the Office must show that an invention would have been obvious to a person of ordinary skill in the art at the time of the invention. MPEP § 2141. It is well known that to establish a prima facie case of obviousness, there must be some suggestion or motivation, either in the references themselves or in the knowledge generally available to one of ordinary skill in the art, to modify the reference or to combine reference teachings. Second, there must be a reasonable expectation of success. The teaching or suggestion to make the claimed combination and the reasonable expectation of success must both be found in the prior art, not in Applicant's disclosure. In re Vaeck, 947 F.2d 488, 20 USPQ2d 1438 (Fed. Cir. 1991). Recently, the Federal Circuit instructed that in technologies that are unpredictable, the standard for a reasonable expectation of success by combining separate references is higher. Novartis Pharm. v. West-Ward Pharm. (923 F.3d 1051 (Fed. Cir. 2019)). At the outset, present claim 1 is directed to a method of treating a subject who has primary melanoma, wherein the primary melanoma is cutaneous melanoma and is stage I to IIC. The method described in claim 1 comprises the steps of: obtaining a biopsy sample from the primary melanoma, determining the T cell fraction (TCFr) of the sample, selecting a subject with TCFr below 20% for an aggressive treatment, and treating that subject with the aggressive treatment. Claim 1 further describes that determining the TCFr comprises analyzing T-cell receptor beta (TCR 3) gene sequences in substantially every T cell in the sample, and quantitating total nucleated cells and calculating the proportion of T cells in the sample relative to its total number of nucleated cell; and specifies that the aggressive treatment is targeted treatment, immunotherapy, chemotherapy, and/or radiation, or a combination thereof. In response to the statement in the Office Action that "no limiting definition is provided for the term "reference level"", Applicant respectfully submits that claim 1, at least as presently amended, requires "selecting a subject with TCFr below 20% for an aggressive treatment; and treating said subject with the aggressive treatment", and thus provides "limiting definition" for the term "reference level". Applicant further submits that Tarhini fails to teach or suggest a method of treating a subject who has stage I to IIC primary melanoma-as required by instant claim 1. Tarhini describes "a randomized trial to evaluate the safety profile and efficacy of combination immunotherapy with high dose IFNa -2b (HDI) and ipilimumab at 3 mg/kg or 10 mg/kg, as a neoadjuvant therapy for locally/regionally advanced operable melanoma" (see, Tarhini, e.g., on Page 2 of 10, right column; emphasis added). Under the Methods section, Tarhini describes the "Patients" as "presented with clinically detectable locally and/or regionally advanced melanoma (cutaneous, mucosal or unknown primary) including (1) Tx or T1-4 and (2) Nib, or N2b, or N2c, or N3 and (3) MO (AJCC 7th edition)". Furthermore, at Table 1 of Tarhini ("Patient demographics and baseline disease characteristics"; see, Tarhini, e.g., at Page 4 of 10, left column), the Estimated risk Stage of the patients is noted as stage IIIB (10% of patients), stage IIIC (83% of patients), and stage IV (7% of patients). Table 1 of Tarhini is copied below for convenience of the Office. Table 1 Patient demographics and baseline disease characteristics SVG {EMBED HERE} 0.5473.797Cutaneous primary 21 (70) Unknown primary 8 (27) Mucosal 1 (3) Gender Female 12 (40) Male 18 (60) Performance status 0 16 (53) 1 14 (47) Recurrent disease after prior surgery 15 (50) Presence of in-transit metastases 16 (53) Prior adjuvant HDI 5 (17) Estimated risk Stage IIIB 3 (10) IIIC 25 (83) IV (Not eligible) 2 (7) Thus, the study described in Tarhini was designed for and executed in patients with advanced melanoma (e.g., stage IIIB, stage IIIC, or stage IV) with lymph node involvement (e.g., "Nlb, or N2b, or N2c, or N3"). Even under the "Conclusion" section, Tarhini states that, "Neoadjuvant immunotherapy with ipilimumab and HDI for patients with locally-regionally advanced melanoma exhibits promising pCR and radiologic response rates at both 3 and 10 mg/kg dosage levels of ipilimumab". The instant claims, on the other hand, are directed to a method for treating a subject who does not have advanced melanoma, but stage I to IIC primary melanoma, which does not involve lymph nodes (see, specification as originally filed, e.g., at "Table A. Exemplary Melanoma Staging Scheme"). Applicant respectfully submits that Tarhini does not teach or even suggest that the method described there could be used to evaluate the efficacy of immunotherapy for patients who do not have advanced melanoma, much less for subjects with stage I to IIC primary melanoma, as required by the instant claims. With no guidance in Tarhini that the method described there could be useful for determining efficacy of treatment in subjects who do not have advanced melanoma (e.g., stage IIIB, stage IIIC, or stage IV, as described in Table 1 of Tarhini), a person of skill in the art would have had no motivation or reason to use Tarhini's method for treating a subject who has stage I to IIC primary melanoma, much less, selecting a subject with TCFr below 20% for an aggressive treatment, and treating the subject with the same - as required by the instant claims. Applicants further submit that the motivation to use Tarhini's method - that evaluates safety profile and efficacy of combination immunotherapy for advanced operable melanoma (e.g., stage IIIB, stage IIIC, or stage IV melanoma with "Nib, or N2b, or N2c, or N3" lymph node involvement) - in a method for treating a subject with stage I to IIC primary melanoma, as required by the instant claims, could only result from hindsight following the teachings of the present specification (and not from the cited reference or knowledge generally available to the person of skill in the art at the time of filing of this application). The Federal Circuit has repeatedly held that it is impermissible to use the claimed invention as an instruction manual or template to piece together the teachings of the prior art so that the claimed invention is rendered obvious. The Court stated that "[o]ne cannot use hindsight reconstruction to pick and choose among isolated disclosures in the prior art to deprecate the claimed invention." In re Fritech, 23 USPQ2d 1780, 1784 (Fed. Cir. 1992) (quoting In re Fine, USPQ 2d 1596, 1600 (Fed. Cir. 1988)). More recently, the Federal Circuit instructed that, "Obviousness requires more than a mere showing that the prior art includes separate references covering each separate limitation in a claim under examination. Rather obviousness requires the additional showing that a person of ordinary skill at the time of the invention would have selected and combined those prior art elements to yield the claimed invention." Unigene Laboratories, Inc v. Apotex, Inc., 655 F.3d 1352 (Fed. Cir. 2011). Applicants submit that the Office, contrary to Federal Circuit guidance, has improperly used the disclosure of the instant application to use the teachings of Tarhini in an attempt to establish a prima facie case of obviousness against the claims. Absent the teachings of the present disclosure, one of skill in the art would not have had any motivation to arrive at the claimed invention based on disclosure of Tarhini. In view of the above, Applicant submits that claim 1 and claims depending therefrom (i.e., claims 5, 8, 10-13, and 15) are inventive over Tarhini, at least because Tarhini does not provide any teaching or suggestion with respect to a method, as claimed in present claim 1. Reconsideration and withdrawal of the rejection is thus kindly requested. Rejection over Tarhini in view of Wang Claim(s) 13 was rejected under 35 U.S.C. § 103 as allegedly obvious over Tarhini as applied to claims 1-15, above, and further in view of Wang et al (US 2016/0354409 Al; "Wang"). In particular, while acknowledging that Tarhini "does not teach administration of a peptide-based or viral-vector based vaccine", the Office cited Wang and alleged "Wang et al discloses use of a peptide based vaccine and viral vector-based vaccine in treating cancers, including melanoma...". Office Action at pages 7-8. Applicant respectfully traverses the rejection for at least the following reasons. Present claim 13 depends from claim 1 and carries all limitations thereof. The deficiencies of Tarhini in rendering claim 1 (and claims dependent therefrom) as obvious is discussed under the "Rejection over Tarhini" section above. Applicant respectfully submits that Wang fails to remedy the deficiencies of Tarhini. Wang describes "peptide and portions thereof recognized as a MHC class II restricted T cell epitope by CD4 T lymphocytes... [that] are encoded within or by a portion of the NY ESO-1 (term used interchangeably herein with CAG-3) gene..., or variants or homologs thereof such as LAGE gene" (see, Wang, e.g., under Summary). As indicated above, this reference was cited by the Office for describing "peptide-based or viral-vector based vaccine". Nowhere does Wang describe, or even suggest, a method that would have motivated or provided reasons to a person of skill in the art to use Tarhini's method - that evaluates safety profile and efficacy of combination immunotherapy for advanced operable melanoma (e.g., stage IIIB, stage IIIC, or stage IV melanoma with "Nib, or N2b, or N2c, or N3" lymph node involvement) - in a method for treating a subject with stage I to IIC primary melanoma, as required by the instant claims. Accordingly, Wang fails to remedy the deficiencies of Tarhini. Thus, Tarhini and Wang, alone or in any combination, fail to render claim 1 and claims dependent therefrom (e.g., claim 13) as obvious. In view of the comments above, the Office is respectfully requested to withdraw the rejection of claim 13 under 35 U.S.C. § 103 as obvious over Tarhini in view of Wang. Claim Rejections - 35 U.S.C. & 101 Claims 1-15 were rejected under 35 U.S.C. § 101 as allegedly directed to an abstract idea without significantly more. In particular, the Office alleged (Office Action at pages 8-9): With regard to claim 1 and its dependent claims, while the claimed method includes a preamble of "treating a subject who has primary melanoma", the final step of the claim states "treating said subject... .when the TCFr is greater than a reference level", such that the claim explicitly does not require a treatment in all cases (rather, the claim clearly includes a conditional limitation, where at least some patients would not receive treatment). As such, this claim recites and encompasses something that could be performed entirely in the human mind, i.e., deciding to not provide treatment based on test results, which is an abstract idea Independent claims 2-3 also recite abstract ideas, claim 2 of "selecting a subject" for treatment, and claim 3 of "identifying a subject... .as likely to progress to metastatic melanoma"; both of these activities could also be performed entirely in the human mind. Applicant respectfully disagrees. Nonetheless, without acquiescing to the rejection and solely in furtherance of prosecution, Applicant has amended independent claim 1 for clarity. As presently amended, independent claim 1 recites: 1. A method of treating a subject who has primary melanoma, wherein the primary melanoma is cutaneous melanoma and is stage I to IIC, the method comprising: obtaining a biopsy sample from the primary melanoma; determining the T cell fraction (TCFr) of said sample, wherein determining the TCFr comprises analyzing T-cell receptor beta (TCR 3) gene sequences in substantially every T cell in the sample, and quantitating total nucleated cells and calculating the proportion of T cells in the sample relative to its total number of nucleated cell; selecting a subject with TCFr below 20% for an aggressive treatment; and treating said subject with the aggressive treatment, wherein the aggressive treatment is targeted treatment, immunotherapy, chemotherapy, and/or radiation, or a combination thereof. Thus, at least as presently amended, claim 1 does not recite any "conditional limitation", but rather require active steps of "selecting a subject with TCFr below 20% for an aggressive treatment; and treating said subject with the aggressive treatment". Applicant respectfully submits that the "treatment" step of present claim 1 integrates any alleged judicial exception into a practical application. Accordingly, at least in light of the aforementioned amendments, claim 1 and claims dependent therefrom are directed to patent-eligible subject matter. Reconsideration and withdrawal of the rejection of these claims under 35 U.S.C. § 101 is thus kindly requested. As has been mentioned in foregoing sections of this response, independent claims 2 and 3 are presently cancelled, thus rendering all rejections directed to these claims moot. CONCLUSION It is believed that all rejections of the pending claims have been addressed. However, the absence of a reply to a specific rejection, issue or comment does not signify agreement with or concession of that rejection, issue or comment. In addition, because the arguments made above may not be exhaustive, there may be reasons for patentability of any or all pending claims (or other claims) that have not been expressed. Finally, nothing in this paper should be construed as intent to concede any issue with regard to any claim, except as specifically stated in this paper, and the amendment of any claim does not necessarily signify concession of unpatentability of the claim prior to its amendment. In view of the preceding arguments and amendments, the claims are believed to be in condition for allowance. If a discussion would be helpful to move the case forward, the Examiner is invited to call the undersigned at the telephone number provided below. The fees for extension of time are being paid with this reply on the USPTO patent electronic filing system. Apply those fees and any other necessary charges or credits to Deposit Account 06-1050, referencing the above attorney docket number. Respectfully submitted, Date: June 20, 2024 /Pallavi Banerjee/ Pallavi Banerjee, Reg. No. 81,012 Customer Number 26161Fish & Richardson P.C. Telephone: +1 (617) 521-7023 Facsimile: (877) 769-7945 24361882.doc

NEXT OFFICE ACTION: FINAL ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This action is responsive to the Amendments and Reply filed June 20, 2024.  Claims 1, 5, 8, 10-13, and 15 have been amended, and claims 2-4, 6-7, 9, and 14 have been canceled.  Claims 1, 5, 8, 10-13, and 15 remain under consideration.  Applicant’s amendments and arguments have been thoroughly reviewed, and have overcome the prior rejections of claims under 35 USC 112(b) (although the claims remain indefinite for the reasons given below), and under 35 USC 103 (in view of the amendment of claim 1 to recite the type of primary melanoma required, as well as more particular criteria for selecting a subject for “aggressive treatment”).  However, the claims remain rejected for the reasons that follow, which include new grounds of rejection necessitated by Applicant’s amendments.  Any rejections and/or objections not reiterated in this action have been withdrawn.  This action is FINAL.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Objections
Claims 1, 5, 8, 10-13, and 15 are objected to because of the following informalities: in independent claim 1, at line 7, the claim recites “total number of nucleated cell” rather than “total number of nucleated cells”.  Appropriate correction is required.
Claim Rejections - 35 USC § 112(d)/fourth paragraph
THE FOLLOWING INCLUDES NEW GROUNDS OF REJECTION NECESSITATED BY APPLICANT’S AMENDMENTS
Claim 15 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.  Amended claim 15 recites “treating a subject with the aggressive treatment when” certain conditions are met; however, claim 1 as written, from which claim 15 depends, actually requires that a “treating” step be performed.  As such, claim 15 does not properly depend from claim 1, as the claim encompasses embodiments in which treating is not performed (specifically, in cases when the criteria specified in claim 15 are not met).  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 § 112(b)/second paragraph
THE FOLLOWING INCLUDES NEW GROUNDS OF REJECTION NECESSITATED BY APPLICANT’S AMENDMENTS:
Claims 1, 5, 8, 10-13, and 15 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.
The term “high” in claim 15 is a relative term that renders the claim indefinite. The term “high” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Accordingly, clarification is required with regard to what would/would not be considered “high” with regard to each of the criteria, or with what a comparison is made in order to establish that a value for one of the criteria is “high”, etc. (although it is also noted that the claim is not properly dependent from claim 1 for the reasons indicated above; thus, both the rejections under 35 USC 112(b) and 35 USC 112(d) should be considered when amending the claim).
Claims 1, 5, 8, and 10-13 are indefinite to the extent that they are directed to embodiments as set forth in dependent claim 15.  Particularly, while the language of independent claim 1 appears to recite a requirement for performing a step of “selecting a subject…for aggressive treatment” and “treating said subject with the aggressive treatment”, dependent claim 15 as written embraces embodiments wherein a treatment identified by the same terminology - “aggressive treatment” - is only performed when additional criteria referenced in that claim are met.  Thus, to the extent that claim 1 and its other dependent claims are directed to such an embodiment, it is unclear what is required by the recitation “treating said subject with the aggressive treatment”, and further clarification (either of claim 1, claim 15, or both) is required.
Claim Rejections - 35 USC § 101
THE FOLLOWING INCLUDES NEW GROUNDS OF REJECTION NECESSITATED BY APPLICANT’S AMENDMENTS:
Claims 1, 5, 8, 10-13, and 15 remain rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Initially, it is noted that this rejection applies to claims 1, 5, 8, and 10-13 to the extent that they are directed to embodiments in which performance of the recited “aggressive treatment” is not actually required, as is suggested by the language of dependent claim 15 (see also the above rejections under 35 USC 112(d) and 35 USC 112(b)).
Claim 15 recites the activity of “treating a subject with the aggressive treatment when the one or more of Breslow thickness, ulceration status, levels of mitoses/mm2, and nodal disease is high” in a sample.  This conditional limitation encompasses embodiments in which an active “treating” is performed, as well as embodiments in which - based on the results of a prior data gathering activity - a decision could be made to take no further action, i.e., a mental activity that may be performed entirely in the human mind, which is a type of abstract idea.  The judicial exception is not integrated into a practical application because the only clearly required active steps of the claims are data gathering steps that amount to insignificant extra-solution activity.  The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because these data gathering steps, whether considered individually or in combination, were well-understood, routine and conventional at the time of applicant’s invention (as evidenced by the teachings of Tarhini et al [previously cited]); the inclusion of these steps in the claims thus does not add anything significantly more than a judicial exception.  Thus, claim 15 - and to the extent that they are directed to the embodiment of claim 15, claims 1, 5, 8, and 10-13 - is/are not directed to patent eligible subject matter.  With further regard to claim 5, this claim is further limiting only of the source of material for data gathering, which does not impart any kind of practical application or add anything more than a JE.   The activities of claim 8 are a more particular type of data gathering known in the art, as evidenced by Tarhini et al.  Regarding claims 10-13, it is reiterated that this rejection applies to the claims to the extent that they do not require performance of the “aggressive treatment” (which again, is in question because of the language of applicant’s claims).
The reply of June 20, 2024 traverses the prior rejection of claims under 35 USC 101 for the following reasons.
The reply summarizes the prior rejection and the language of independent claim 1 as amended (Reply page 12), and urges that amended claim 1 does not recite a conditional limitation, but rather active steps of “selecting a subject with TCFr below 20% for an aggressive treatment” and “treating said subject with the aggressive treatment”, such that the “treatment” of the claim “integrates any alleged judicial exception into a practical application” (Reply at page 12 bridging to page 13).
These arguments have been thoroughly considered but are not persuasive, because - as is indicated in the above rejections - the amended claims (and particularly claim 15, as well as claims 1, 5, 8, and 10-13 as directed to embodiments as set forth in claim 15) do not clearly necessarily require performance of the recited “aggressive treatment” in the manner referenced in claim 1.  Accordingly, given the actual language of the claims under consideration, the rejection must be maintained.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action.  Accordingly, THIS ACTION IS MADE FINAL.  See MPEP § 706.07(a).  Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action.  In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action.  In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.

CITED REFERENCE SUMMARIES: Ref US20160354409A1: Claims:
1.-6. (canceled)
7. A method of treating or preventing cancer in a mammal, the method comprising administering one or more cells to the mammal in an amount effective to treat or prevent cancer in the mammal,
wherein the cell is an isolated or purified cancer antigen specific human CD4+ T lymphocyte immunoreactive with an HLA-DP restricted NY-ESO-1 peptide comprising Xaa1ITQXaa2FXaa3PXaa4 (SEQ ID NO: 51), wherein Xaa1 is Trp, Xaa2 is Cys, Xaa3 is Leu, Xaa4 represents at least one amino acid, and wherein the peptide consists of 9-30 amino acid residues and is immunologically recognized by HLA-DP restricted CD4+ T lymphocytes.
8. The method of claim 7, wherein the NY-ESO-1 peptide consists of 9-30 amino acid residues and comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 53-64 and X0-WITQCFLPVF-X5 (SEQ ID NO: 52), wherein X0 and X5 each represent one or more naturally occurring amino acids.
9. The method of claim 7, wherein the NY-ESO-1 peptide consists of the amino acid sequence of SEQ ID NO: 54.
10. The method of claim 7, wherein the cancer expresses NY-ESO-1.
11. The method of claim 7, wherein the cancer is thymoma, lymphoma or sarcoma.
12. The method of claim 7, wherein the cancer is lung cancer, liver cancer, or non-Hodgkin's lymphoma.
13. The method of claim 7, wherein the cancer is Hodgkins lymphoma, leukemia, or uterine cancer.
14. The method of claim 7, wherein the cancer is cervical cancer, bladder cancer, or kidney cancer.
15. The method of claim 7, wherein the cancer is head and neck cancer, neuroblastoma, or adenocarcinoma.
16. The method of claim 7, wherein the cancer is breast cancer, prostate cancer, or ovarian cancer.
17. The method of claim 7, wherein the cancer is pancreatic cancer or thyroid cancer.
18. The method of claim 7, wherein the cancer is melanoma.
19. The method of claim 18, wherein the melanoma is primary melanoma.
20. The method of claim 18, wherein the melanoma is metastatic melanoma.
21. The method of claim 18, wherein the melanoma is melanocarcinoma.
22. The method of claim 18, wherein the melanoma is melanoepithelioma.
23. The method of claim 18, wherein the melanoma is melanosarcoma.
24. The method of claim 18, wherein the melanoma is melanoma in situ.
25. The method of claim 18, wherein the melanoma is superficial spreading melanoma.
26. The method of claim 18, wherein the melanoma is nodular melanoma, lentigo maligna melanoma, or acral lentiginous melanoma.
Ref APP-16_838926: Claims:
A method of treating a subject who has primary melanoma, the method comprising: obtaining a biopsy sample from the primary melanoma; determining the T cell frequency (TCFr) of said sample; and treating said subject with an aggressive treatment when the TCFr is greater than a reference level.
obtaining a biopsy sample from the primary melanoma;
determining the T cell frequency (TCFr) of said sample; and
treating said subject with an aggressive treatment when the TCFr is greater than a reference level.
A method of selecting a subject with primary melanoma for aggressive treatment, the method comprising: obtaining a biopsy sample from the primary melanoma; determining the T cell frequency (TCFr) of said sample; and selecting a subject who has a TCFr below a reference level for aggressive treatment.
selecting a subject who has a TCFr below a reference level for aggressive treatment.
A method of predicting whether a subject with primary melanoma is likely to progress to metastatic melanoma, the method comprising: obtaining a biopsy sample from the primary melanoma; determining the T cell frequency (TCFr) of said sample; and identifying a subject who has a TCFr below a reference level as likely to progress to metastatic melanoma.
identifying a subject who has a TCFr below a reference level as likely to progress to metastatic melanoma.
The method of claim 1, wherein the primary melanoma is cutaneous melanoma.
The method of claim 4, wherein the primary melanoma is 1-4 mm thick.
The method of claim 5, wherein the primary melanoma is stage I to IIC.
The method of claim 1, wherein determining the T cell frequency (TCFr) of said skin sample comprises analyzing T-cell receptor beta (TCR β) gene sequences in substantially every T cell in the sample, quantitating total nucleated cells and calculating the proportion of T cells in the sample relative to its total number of nucleated cells.
The method of claim 7, wherein said analyzing is performed by high-throughput DNA sequencing.
The method of claim 1, wherein the aggressive treatment is targeted treatment, immunotherapy, chemotherapy, and/or radiation, or a combination thereof.
The method of claim 9, wherein the chemotherapy comprises administration of one or more nitrosoureas; alkylating agents; microtubule targeting agents; or platinum-containing agents.
The method of claim 9, wherein the targeted treatment comprises a BRAF inhibitor and/or a MEK inhibitor.
The method of claim 9, wherein the immunotherapy comprises administration of a checkpoint inhibitor.
The method of claim 9, wherein the immunotherapy comprises administration of a vaccines targeting melanoma cells, peptide-based vaccine, viral vector-based vaccine, or dendritic cell vaccine.
The method of claim 1, wherein the reference level is 20%.
The method of claim 1, further comprising determining one or more of Breslow thickness; ulceration status; levels of mitoses/mm2; and nodal disease in the sample, and determining prognosis or selecting therapy based on TCFr and Breslow thickness; ulceration status; levels of mitoses/mm2; and/or nodal disease in the sample.
Ref APP62828064: [content unavailable]