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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/24/2025 has been entered.
Election/Restrictions
Applicant’s election of Group (I) along with lung tumor or lung cancer that is EGFR
mutated and ALK fusion driven and SHP099 is maintained.
Priority
This application claims priority from U.S. Provisional Application Serial No. 63/010,214 filed on 15 April 2020.
Status of Claims
Claims 1-3 and 5-18 are pending. Claims 4 and 19 are canceled. Claims 8-17 are withdraw. Claims 1-3, 5-7, and 18 are examined in accordance to the elected species.
Response to Arguments
Applicant’s arguments filed 01/02/2025 have been fully considered. Rejections and objections not reiterated form previous Office Action are hereby withdrawn. The following rejections are either reiterated or newly applied. They constitute the complete set of rejections presently being applied to the instant application.
Drawings
The drawings are objected to as being of poor quality and not suitable for reproduction. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
In the present case, although the drawings appear to be acceptable in color format, the figures in the drawing appear to be overly crowded and contain densely packed graphical elements and text, such that the details are not clearly legible. Additionally, the drawings appear to be faded and lack sufficient contrast, rendering certain features, labels, and data point difficult to discern.
Claim Rejections - 35 USC § 112
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, and 18 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 of said claim recites “upregulated phosphorylation of PTPN11 is detected by measuring increased phosphorylation levels of PTPN11 at a residue selected from the group consisting of:
Y62 and Y546;
Y62 and Y584;
and Y62, Y546, and Y584.
However, the specification does not reasonably convey possession of the specific combinations of residues.
The specification describes phosphorylation at individual residues, including:
Y62 (e.g., p. 22, lines 1-3; p. 65, liones 29-31_;
Y546, and Y584 (e.g., p. 52; p. 66; p.168). However, the specification does not describe
Or suggest:
The combined measurement of Y62 with Y546;
The combined measurement of Y62 with Y584; or
The simultaneous measurement of Y62, Y546, and T584. Nor does the specification
Provide any teaching that these residues are to be used in combination for detecting PTPN11 activation. The mere disclosure of individual residues does not provide written description support for the specific combinations now claimed, particularly where the invention relates to complex and unpredictable biological signaling pathways.
Accordingly, the specification does not demonstrate that the inventor had possession of the claimed combinations at the time of filing.
Claims 1-3, 5-7, and 18 are under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for measuring increased phosphorylation levels at residue Y62 and at residues Y546 and Y584 in primary lung cancer cell not from a cell line and using SHP2 inhibitors such as SH099, and identifies certain tumor contexts including EGFR-mutated and ALK fusion-driven tumors does not reasonably provide enablement for full scope of the claim. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The specification discloses inhibition of PTPN11 (SHP2), including use of SHP2 inhibitors such as SHP099, and identifies certain tumors contexts including EGFR-mutated and ALK fusion-driven tumors (See Abstract.) These embodiments correspond to the elected species.
However, the claims are substantially broader than the scope of the enabling disclosure. In particular, claim 1 broadly encompasses inhibition of PTPN11 in primary lung cancer generally, without limitation to EGFR-mutated or ALK fusion-driven tumors, and without limitation to SHP099. Further, claim 7 encompases numerous tumor genotypes, biomarkers, and treatment regimens, including KRAS-, TP53-, KEAP-, and STK11-mutated tumors, immune phenotypes, and multiple phosphoprotein-enriched states. (See Figures A1-1F.)
While the specification provides extensive multi-omics profiling data identifying correlations between tumor subtypes and molecular features in (pages 20 and 21 of the PgPub, US20230416250A1), such disclosure does not demonstrate that inhibition of PTPN11 is effective across the full scope of the claimed tumor types and treatment combinations. Rather, the specification provides a research framework for identifying potential therapeutic targets, without enabling their therapeutic use across the claimed breath.
Moreover, the art of cancer treatment is highly unpredictable, particularly with respect to targeted therapies across distinct genetic backgrounds. It is well established that tumors driven by different oncogenic mutations (e.g., EGFR, KRAS, TP53, KEAP) exhibit distinct signaling dependencies and differential responses to targeted therapies, such that efficacy in one tumor subtype does not reasonably predict efficacy in others. See Cancer Genome Atlas Research Network (2014) (demonstrating molecular heterogeneity of lung adenocarcinoma and distinct pathway dependencies among subtypes. (See pages 20 and 21 of PbPub, US20230416250A1)
Accordingly, one of ordinary skill in the art would not reasonably expect that inhibition of PTPN11 would be effective across the broad range of tumor genotypes and treatment contexts recited in the claims without extensive experimentation.
Wands’ Factors:
Breath of the claims
Extremely broad, encompassing numerous tumor genotypes and treatment combinations beyond the disclosed SHP099pEGFR/ALK embodiments.
Nature of the Invention
Directed to targeted cancer therapy, where efficacy depends on tumor-specific molecular drivers.
State of the prior art
The art demonstrates molecular heterogeneity and distinct pathway dependencies among tumor subtypes, supporting unpredictability.
Level of skill in the art
Skilled artisans would still require case-by-case validation across tumor types.
Predictability of the art
The art is highly unpredictable, particularly across genetically distinct cancers
Guidance in the specification
Limited to corelative data; lacks therapeutic guidance across the full scope
Working examples
Lacks representative examples across claimed tumor genotypes.
Quantity of experimentation
Would require undue experimentation, including extensive screening of tumor-specific responses.
The specification provides correlative multi-omics data identifying potential targets, but does not enable the claimed methods of treatment across the full scope of tumor types and therapeutic combinations, particular in view of the well-established unpredictability of targeted cancer therapy across distinct genetic subtypes.
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, and 18 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 1 recites “administering a PTPN11 inhibitor to the tumor or tumor cell…” This limitation is ambiguous because it encompasses at least two distinct and materially different interpretations:
1. Administration to a tumor in a subject (in vivo); and
2. Administration to a tumor cell (in vitro or ex vivo).
The claim does not clarify whether the method is directed to treatment of a subject or manipulation of isolated cells, not does it define how “administration” is performed with respect to a tumor cell. Accordingly, the metes and bounds of the claim are unclear.
Further, the disjunctive phrase “tumor or tumor cell” render the scope uncertain, particularly because “administering” is not a conventional therapeutic step when applied directly to isolated cells. Therefore, the claim fails to inform, with reasonable certainty, those skilled in the art of the its scope.
Claims 2, 3 and 5-7, and 18 are rejected for the same reasons.
Additionally, claim 6 recites “the tumor is or the tumor cell is a cell from EGFR-, ALK1-, or PDGFRA-activated tumor.” This language is unclear because it is ambiguous whether the limitation applies to the tumor itself, or a tumor cell derived therefrom. The phrase “tumor is a cell” is internally inconsistent and lacks clear meaning. Accordingly, the scope of the claim cannot be determined with reasonable certainty.
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.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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 non-obviousness.
Claims 1-3, 5-7, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Schneeberger et al (Oncotarget. 2015 Mar 20; 6(8): 6191–6202) in view of Vemulapalli et al (BioRxiv, posted April 12, 2019) and Ren et al (Genes & Cancer 1(10) 994–1007, 2011).
Schneeberger suggests a method of inhibiting PTPN11 (SHP2) in lung adenocarcinoma, including EGFR-mutant tumors, as evidenced by activation of the Gab1-SHP2 pathway in the EGFR inhibitor-resistant lung adenocarcinoma, and that inhibition of SHP2 phosphatase activity suppresses EGFRL858R-driven lung adenocarcinoma. (See Abstract, page 6198, left column, paragraph 3; page 6199, left column paragraph 2.)
Schneeberger does not teach detecting upregulated phosphorylation of PTPN11 by measuring phosphorylation levels compared to a reference sample or value; measuring phosphorylation at specific residues or combination of residues claimed; and administering a specific DHP2 inhibitor such as SH099.
Vemulapalli teaches a selective SHP2 (PTPN11) inhibitor, SHP099 that inhibits SHP2 and downstream signaling, including ERK phosphorylation, and said SHP2 signaling is associated with phosphotyrosine modulation, including residues corresponding Y546 and Y584. (See page 7, last paragraph bridging page 8, first paragraph.)
Thus, Vemulapalli teaches administration of a specific PTPN11 inhibitor (SHP099) and the measurement and functional relevance of phosphorylation levels.
Ren teaches that Shp2 Y62 and Y63 phosphorylation was detected in our H292 tumor xenograft tissues (Fig. 7A and 7B). Since Y62 and Y63 are hidden in the N-SH2 and PTP domain interface in the unliganded Shp2 (Fig. 7C), Shp2 must adapt an open, active conformation in order for these 2 residues to be accessible for phosphorylation, suggesting that Shp2 was activated in the tumors. (See Figures 7A, 7B, and 7C.)
Thus, Ren teaches measuring increased phosphorylation levels of PTPN11/SHP2 at specific residues (e.g., Y62) to detect pathway activation.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the method of Schneeberger to include the specific SHP2 inhibitor SHP099 as taught by Vemulapalli and detection of SHP2 activation via phosphorylation measurement at residues combination claimed as taught by Ren and Vemulapalli. The motivation to combine arises from the recognition that Schneeberger identifies SHP2 as a key driver of EGFR-mutant lung cancer, Vemulapalli provides a specific inhibitor (SHP099) for targeting SHP2, and Ren and Vemulapalli teach that phosphorylation levels serve as indicators of SHP activation. One would have a reasonable expectation of success because SHP2 inhibition was already known to suppress tumor growth as taught by Schneeberger, SHP099 was known to effectively inhibit SHP2 activity as taught by Vemulapalli, and phosphorylation assays were routine techniques for monitoring signaling pathways as taught by Ren.
The selection and combination of known SHP2 phosphorylation sites (e.g., Y62, T546, and Y584) represents the use of multiple known biomarkers to assess pathway activation, which would have been obvious to one of ordinary skill in the art.
Claim 7 recites conditional limitations (i.e., “if” clauses). Such limitations require the recited treatment step only when the stated condition is met and do not limit the claim when the condition is not satisfied.
Claim 18 under the broadest reasonable interpretation, the recitation of “tumor or tumor cell” encompasses both tumor tissue and tumor-derived cells, and therefore reads on the prior art disclosing either context. So, the recitation of “tumor or tumor cell” in claim 18 broadly encompasses both in vivo tumors and isolated tumor cell, and thus, does not patentably distinguish over the prior art, which teaches treatment and/or analysis of tumor cells.
Applicant argues that the Office has failed to address the requirement of measuring at least one of the cited combination residues Y546 and/or Y584 in addition to the requirement of measuring the Y62 residues, and the cited combination of references is silent to these residues.
Applicant’s argument is not persuasive. While Ren teaches phosphorylation at residue Y62 as indicative of SHP2 activation, the combination of references relied upon in the new rejection further includes teachings directed to additional phosphorylation sites of PTPN11 (SHP2), including residues corresponding to Y546 and Y58. See Vemula and/or He) Thus, the applied prior art collectively teaches phosphorylation at multiple residues associated with SHP2.
To the extent Applicant contends that the specific combination is not expressly disclosed, the rejection relies on the combined teachings of the references, which identify these residues as associated with SHP2 activity. A person of ordinary skill in the art would have had a reasonable expectation of success in measuring these residues together, as each was known to reflect SHP2 activation, and their combined assessment would predictably provide confirmatory information regarding pathway activity.
Accordingly, the selection of Y62 in combination with one or more additional known SHP2 phosphorylation sites, such as T546 and/or Y584, constitutes nothing more than predictable use of the prior art elements according to their established functions. See KSF Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007).
Conclusion
Claims 1-3, 5-7, and 18 are not allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEAN P CORNET whose telephone number is (571)270-7669. The examiner can normally be reached Monday-Thursday from 7.00am-5.30pm.
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/JEAN P CORNET/ Primary Examiner, Art Unit 1628
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