DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
2. Applicant’s election without traverse of the species of methods wherein 9p-arm loss is detected by assessing loss of 9p21.3; methods of assessing loss of 9p21.3 by detecting deletion of the MLLT3, LEAVL2 or KLH9 gene; and methods which further assess cell-intrinsic senescence-associated secretory pathway (SASP) suppression in the reply filed on 10 April 2026 is acknowledged.
Claim Status
3. Claims 1-20 and 47-50 are pending.
Claims 8-10, 13-20, and 47 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. It is noted that the restriction requirement inadvertently listed claim 8 as a generic claim at page 8. However, claim 8 recites the non-elected species of methods that further assess suppression of IFN-γ-induced CXCL9/10 expression and thereby is not a generic claim to the recited species.
Claims 1-7, 11, 12, and 48-50 read on the elected invention and have been examined herein.
Priority
4. The present specification states “This application is a U.S. National Phase Application under 35 U.S.C. Q 371 of International Patent Application No. PCT/US2022/015363, filed February 4, 2022, which claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application Serial Nos. 63/146,191, filed February 5, 2021 and 63/179,215, filed April 24, 2021.”
However, the filing receipt is not consistent with this statement since the filing receipt does not list the claim to priority to the provisional applications. A portion of which is included below:
PNG
media_image1.png
130
664
media_image1.png
Greyscale
Note that t the filing receipt serves as the official USPTO acknowledgment of a patent application's priority or benefit claim.
As stated in MPEP 503, “Applicants are encouraged to check their filing receipts for accuracy with particular attention to the inventor’s and applicant’s names, benefit and priority claims, and whether or not a nonpublication request, if submitted, was recognized.” Also, MPEP 211 III states “If applicant receives a filing receipt with incorrect information regarding the 37 CFR 1.55/1.78 statement, applicant may request a corrected filing receipt. Therefore, applicants should carefully and promptly review their filing receipts in order to ensure that their applications will be examined under the correct statutory framework.
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
5. Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825 because it does not contain a "Sequence Listing" as a separate part of the disclosure or a CRF of the “Sequence Listing.”.
Note that the specification includes amino acid sequences greater than 4 amino acids in length - for example at para [0082] and [0083]. However, no Sequence Listing has been filed in this application.
Required response - Applicant must provide:
A "Sequence Listing" part of the disclosure; together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(a)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.821(a)(4); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(a)(3).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
If the "Sequence Listing" part of the disclosure is submitted according to item 1) c) or d) above, applicant must also provide:
A CRF in accordance with 37 CFR 1.821(e)(1) or 1.821(e)(2) as required by 1.825(a)(5); and
A statement according to item 2) a) or b) above.
2) Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). See, for example, para [0082] and [0083].
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
6. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code – see, for example, para [0052] and [0093]. 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, such as “www.”. See MPEP § 608.01.
Drawings
7. The drawings are objected to because the content of the drawings is extremely faint / in a very light color and blurry and the details / wording in the drawings are not clear. 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.
Claim Objections
8. Claims 1, 2, 5, 7, and 11 are objected to because of the following informalities:
Claims 1, 2, 5, 7, and 11 refer interchangeably to a “subject” and a “patient” whereas the claims should refer consistently to one or the other. Appropriate correction is required.
In particular, the objection may be overcome by amendment of claims 1 and 2 to recite “if a sample isolated from the subject” in place of “if a sample isolated from the patient.”
Claim Rejections - 35 USC § 101
9. 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 1-7, 11, 12 and 48-50 are rejected under 35 U.S.C. 101 because the claimed invention is directed to the judicial exception of a law of nature / natural phenomenon, and/or an abstract idea without significantly more. The judicial exception is not integrated into a practical application and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow.
Applicant' s attention is directed to MPEP 2106 “Patent Subject Matter Eligibility” which discusses the Alice/Mayo two-part test for evaluating subject matter eligibility.
Regarding Step 1 of the subject matter eligibility test set forth at MPEP 2106III, the claims are directed to the statutory category of a process.
Regarding Step 2A, prong one, the claims recite the judicial exception of a law of nature. The claims recite the correlation between 9p-arm loss or loss of a part of 9p and responsiveness to a PD-1/PD-L1 centered therapy. For example, claim 1 requires administering PD-1/PD-L1 centered immunotherapy to the subject if a sample isolated from the patient comprising the cancer cell does not show 9p-arm loss; claim 2 requires administering a therapy to the subject that does not comprise PD-1/PD-L1 centered immunotherapy to the subject if a sample isolated from the patient comprising the cancer cell shows 9p-arm loss; claim 3 requires administering PD-1/PD-L1 centered immunotherapy if the degree of 9p-arm loss does not show significant 9p-arm loss; claim 48 requires administering to the subject treatment that does not comprise PD-1/PD-L1 centered immunotherapy if the degree of 9p-arm loss shows significant 9p-arm loss; and claims 49 and 50 require determining that a subject or a type of cancer will respond to administering PD-1/PD-L1 centered immunotherapy if the degree of 9p-arm loss does not show significant 9p-arm loss.. As in Mayo Collaborative Services v. Prometheus, the recited relationship is a natural phenomenon that exists apart from any human action. See also Cleveland Clinic Foundation v. True Health Diagnostic, LLC, 2018-1218 (Fed Cir. 2019) which states that “The re-phrasing of the claims does not make them less directed to a natural law.”
The claims also recite the judicial exception of an abstract idea and particularly mental processes.
MPEP 2106.04(a) states that the enumerated groupings of abstract ideas include:
“1) Mathematical concepts – mathematical relationships, mathematical formulas or equations, mathematical calculations (see MPEP § 2106.04(a)(2), subsection I);…
3) Mental processes – concepts performed in the human mind (including an observation, evaluation, judgment, opinion) (see MPEP § 2106.04(a)(2), subsection III).”
The claims require performing the step of “determining” the level of expression of one or more biomarkers. Neither the specification nor the claims set forth a limiting definition for "determining" and the claims do not set forth how “determining” is accomplished. The broadest reasonable interpretation of the determining step is that this step may be accomplished by reading information in a database or report to thereby ascertain the level of expression of the genes in a sample obtained from a subject. Such “determining” thereby encompasses processes that may be performed mentally and thus is an abstract idea.
Claims 3, 4, 6 and 48-50 require “determining” the degree of 9p-arm loss. Claims 49 and 50 also require “predicting” or “determining” whether a cancer will respond to therapy. Claim 11 requires “assessing” SASP suppression and claim 12 requires assessing a deletion of a gene. Neither the specification nor the claims set forth a limiting definition for "determining," “predicting,” or “assessing.” and the claims do not set forth how “assaying” is accomplished. The claims do not specifically require performing an active laboratory process in which expression levels are detected. The broadest reasonable interpretation of the "determining," “predicting,” and “assessing” steps is that these steps may be accomplished by critical thinking processes and thereby are an abstract idea.
In claims 49 and 50, the predicting or determining whether a subject (claim 49) or type of cancer (claim 50) may also be accomplished verbally. Such verbal communication is also abstract, having no particular concrete or tangible form.
Regarding Step 2A, prong two, having determined that the claims recite a judicial exception, it is then determined whether the claims recite additional elements that integrate the judicial exception into a practical application.
Herein, the claims do not recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s).
In claims 1-3, the claims require that the administering step is performed only “if” 9p-arm loss is present. However, claim 1 does not require that the cancer cell does not show 9p-arm loss; claim 2 does not require that the sample shows 9p-arm loss and claim 3 does not require that the sample does not show significant 9p-arm loss. Thus, claims 1 and 2 encompass methods in which no steps are performed. Claim 3 encompasses methods which requires only the measuring step and the measuring indicates that there is significant 9p-arm loss.
Similarly in claim 48, the administering step only occurs if the degree of 9p-arm loss shows significant 9p-arm loss. Claim 48 does not require that the method is one in which it is determined that there is significant 9p-arm loss.
In claims 3 (and the claims that depend thereon) and claims 48-50, the measuring step is part of the data gathering process necessary to observe the judicial exception. The measuring step does not practically apply the judicial exception.
Further, in claims 2 and 48, the claims encompass administering any therapy that does not comprise PD-1/PD-L1 centered immunotherapy. As broadly recited, the therapy may be essentially any therapy that does not comprise “PD-1/PD-L1 centered immunotherapy.” As broadly recited the administering step does not constitute a practical application of the judicial exception. Rather, this is merely an “apply it” limitation.
Regarding specific treatments, see MPEP 2106.04(d)(2):
When determining whether a claim applies or uses a recited judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition, the following factors are relevant.
a. The Particularity Or Generality Of The Treatment Or Prophylaxis
The treatment or prophylaxis limitation must be "particular," i.e., specifically identified so that it does not encompass all applications of the judicial exception(s). For example, consider a claim that recites mentally analyzing information to identify if a patient has a genotype associated with poor metabolism of beta blocker medications. This falls within the mental process grouping of abstract ideas enumerated in MPEP § 2106.04(a). The claim also recites "administering a lower than normal dosage of a beta blocker medication to a patient identified as having the poor metabolizer genotype." This administration step is particular, and it integrates the mental analysis step into a practical application. Conversely, consider a claim that recites the same abstract idea and "administering a suitable medication to a patient." This administration step is not particular, and is instead merely instructions to "apply" the exception in a generic way. Thus, the administration step does not integrate the mental analysis step into a practical application….
b. Whether The Limitation(s) Have More Than A Nominal Or Insignificant Relationship To The Exception(s)
The treatment or prophylaxis limitation must have more than a nominal or insignificant relationship to the exception(s). For example, consider a claim that recites a natural correlation (law of nature) between blood glucose levels over 250 mg/dl and the risk of developing ketoacidosis (a life-threatening medical condition). The claim also recites "treating a patient having a blood glucose level over 250 mg/dl with insulin". Insulin acts to lower blood glucose levels, and administering insulin to a patient will reduce the patient’s blood glucose level, thereby lowering the risk that the patient will develop ketoacidosis. Thus, in the context of this claim, the administration step is significantly related to the recited correlation between high blood glucose levels and the risk of ketoacidosis. Because insulin is also a "particular" treatment, this administration step integrates the law of nature into a practical application. Alternatively, consider a claim that recites the same law of nature and also recites "treating a patient having a blood glucose level over 250 mg/dl with aspirin." Aspirin is not known in the art as a treatment for ketoacidosis or diabetes, although some patients with diabetes may be on aspirin therapy for other medical reasons (e.g., to control pain or inflammation, or to prevent blood clots). In the context of this claim and the recited correlation between high blood glucose levels and the risk of ketoacidosis, administration of aspirin has at best a nominal connection to the law of nature, because aspirin does not treat or prevent ketoacidosis. This step therefore does not apply or use the exception in any meaningful way. Thus, this step of administering aspirin does not integrate the law of nature into a practical application.
Regarding Step 2B, the next question is whether the remaining elements/steps – i.e., the non-patent-ineligible elements/steps - either in isolation or combination, amount to significantly more than the judicial exception.
Herein, the claims as a whole are not considered to recite any additional steps or elements that amount to significantly more than routine and conventional activity and do not add something “significantly more” so as to render the claims patent-eligible. Claim 1 does not require performing any specific, non-conventional transformative active process steps in those instances when the cancer cell does not show 9p-arm loss. Claim 2 does not require performing any specific, non-conventional transformative active process steps in those instances when the cancer cell does show 9p-arm loss. Claims 3 and 48-50 require performing a step of measuring 9p-arm loss. However, this step is recited at a high degree of generality and methods for detecting chromosome loss were well-known, routine and conventional in the prior art. The measuring step may be accomplished by conventional methods such performing PCR, hybridization or sequencing. See MPEP 2106.05(d) II which states that:
The courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
i. Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);…
ii. Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);…
v. Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546; …
vii. Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014); and
viii. Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247.
Note that while the claims recite measuring 9p-arm loss, the identity of the chromosomal region is part of the judicial exception and not something in addition to the recited judicial exceptions. The claims do not require using a particular non-conventional reagent, such as a particular, non-conventional probe or primer consisting of or comprising a specific nucleotide sequence so as to add something ‘significantly more’ to the recited judicial exceptions.
In Mayo v. Prometheus, the Supreme Court stated: "[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately."
This is similar to the present situation wherein the additional steps and elements are recited at a high degree of generality and are all routine, well understood and conventional in the prior art. The recited steps and elements do not provide the inventive concept necessary to render the claims patent eligible. See also Genetic Technologies Ltd. v. Merial L.L.C. 818 F.3d at 1377, 1379 (Fed. Cir. 2016).
For the reasons set forth above, when the claims are considered as a whole, the claims are not considered to recite something significantly more than a judicial exception and thereby are not directed to patent eligible subject matter.
Claim Rejections - 35 USC § 112(b) - Indefiniteness
10. 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 1-7, 11, 12 and 48-50 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 1-7, 11 12, and 48-50 are indefinite over the recitation of “PD-1/PD-L1 centered immunotherapy.” This phrase is not defined in the specification or the claims and there is no art recognized definition for this phrase. It is unclear as to whether a ”PD-1/PD-L1 centered immunotherapy” is limited to an immunotherapy that comprises an inhibitor of PD-1 or PD-L1 or if this phrase includes any immunotherapy that directly or indirectly affects any molecule in a PD-1 or PD-L1 pathway or a molecule that interacts with PD-1 or PD-L1, including therapies that activate / enhance PD-1 or PD-L1 activity or expression. It is unclear as to what is intended to be included and what is intended to be excluded by the language of “PD-1/PD-L1 centered immunotherapy.”
Claims 1, 2, 5, 7 and 11 are indefinite over the recitation of “the cancer cell” because this phrase lacks proper antecedent basis since the claims do not previously refer to a cancer cell.
Claims 1, 5, 7 and 11 are indefinite. The claims are drawn to a method for treating cancer in a subject in need thereof. However, the claims recite a single step of administering which occurs “if a sample isolated from the patient comprising the cancer cell does not show 9p-arm loss.” However, the claims do not require that the subject is one in which the cancer cell in the sample from the subject does not show 9p-arm loss. Accordingly, it is not clear as to what is intended to be encompassed by the claims in those embodiments in which the subject does show 9p-arm loss and it is unclear as to how the claims accomplish the objective of treating cancer in those subjects having cancer cells that show 9p-arm loss.
Similarly, claim 2 is indefinite because the claim recites a single step of administering which occurs “if a sample isolated from the patient comprising the cancer cell shows 9p-arm loss..” However, the claim does not require that the subject is one in which the cancer cell shows 9p-arm loss. Accordingly, it is not clear as to what is intended to be encompassed by the claims in those embodiments in which the subject does not show 9p-arm loss and it is unclear as to how the claim accomplishes the objective of treating cancer in those subjects having cancer cells that do not show 9p-arm loss.
Claims 3, 4, 5, 6 and 12 are indefinite. The claims are drawn to a method for treating cancer in a subject in need thereof. However, the claims recite “administering PD-1/PD-L1 centered immunotherapy if the degree of 9p-arm loss does not show significant 9p-arm loss.” However, the claims do not require that the subject is one in which the cancer cell in the sample from the subject does not show significant 9p-arm loss. Accordingly, it is not clear as to what is intended to be encompassed by the claims in those embodiments in which the subject shows significant 9p-arm loss and, in this embodiment encompassed by the claims, it is unclear as to how the claims accomplish the objective of treating cancer in the subjects having cancer cells that show significant 9p-arm loss.
Claims 3, 4, 5, 6 and 12 are indefinite and vague over the recitation of “determining a degree of 9p-arm loss” because it is not stated in what the degree of 9p-arm loss is determined. The claims are also indefinite and vague over the recitation of “administering PD-1/PD-L1 centered immunotherapy” because the claims do not state to whom the immunotherapy is administered.
Claims 3, and 48-50 are indefinite over the recitation of “significant 9p-arm loss” because it is not clear as to what degree of loss of 9p-arm sequences are required to meet the limitation of “significant.” The specification (para [0117]) states that “significant 9p-arm loss comprises 9p21.3 loss, the assessment is associated with immune-cold tumor microenvironment (TME) signal. It is also stated that “[0118] In one aspect, a significant loss of 9p21.3 of the entire 9p arm measured as loss of ≥70% of arm length.” However, these are only examples of what could be encompassed by a “significant 9p-arm loss.” It is unclear as to what degree of loss of 9p-arm chromosomal sequences are included and excluded by the claims.
Claim 7 is indefinite over the recitation of “wherein 9p21.3 loss comprises loss of entire 9p arm measured as loss of >70% of arm length.” First, it is unclear as to what the phrase “wherein 9p21.3 loss” is intended to refer to since the claim does not previously refer to 9p21.3 loss and only previously refers to “9p-arm loss.” Secondly, it is unclear as to how loss of the “entire” 9p arm is intended to be the same as loss of 70% and less than 100% of the 9p-arm. This limitation is confusing and it is not clear as to whether the claim requires loss of the entire / 100% of the 9p arm or includes loss of 70% or more of the 9p-arm.
Claim Rejections - 35 USC § 112(a) - Enablement
11. 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 1-7, 11, 12 and 48-50 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 of treating a subject having HPV- head and neck squamous cell carcinoma (HNSC), the method comprising administering an anti-PD-1 immunotherapy to the subject after a cancer cell sample obtained from the subject is assayed for a deletion of the 9p-arm and it is determined that the subject does not have a deletion of the full length 9p-arm; and a method of treating a subject having HPV- head and neck squamous cell carcinoma (HNSC), the method comprising administering a cancer therapy that is not an anti-PD-1 or anti-PD-L1 immunotherapy to the subject after a cancer cell sample obtained from the subject is assayed for a deletion of the 9p-arm and it is determined that the subject has a deletion of the full length 9p-arm;
does not reasonably provide enablement for the claimed methods of treating any type of cancer by administering PD-1/PD-L1 centered immunotherapy to a subject if a sample isolated from the subject does not show 9p-arm loss or administering any therapy to the subject that does not comprise a PD-1/PD-L1 centered immunotherapy to the subject if a sample isolated from the subject shows 9p-arm loss; or methods of treating any type of cancer or precancer comprising administering PD-1/PD-L1 centered immunotherapy if the degree of 9p-arm loss does not show significant 9p-arm loss, wherein 9p-arm loss is assessed / measured by any method and 9p-arm loss includes loss of any one or more nucleotides or any region within the 9p-arm and a significant 9p-arm loss encompasses any degree of 9p-arm loss. 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 use the invention commensurate in scope with these claims. .
The following factors have been considered in formulating this rejection (In re Wands, 858F.2d 731, 8 USPQ2d 1400 (Fed. Cir. 1988): the breadth of the claims, the nature of the invention, the state of the prior art, the relative skill of those in the art, the predictability or unpredictability of the art, the amount of direction or guidance presented, the presence or absence of working examples of the invention and the quantity of experimentation necessary.
The claims as broadly recited encompass methods which treat cancer patients or predict or determine a response of cancer patients to a “PD-1/PD-L1 centered immunotherapy” based on the detection of 9p-arm loss.
While claims 5 and 6 are limited to methods wherein the cancer is HPV- HNSC, claims 1-4, 7 and 49-50 encompass methods wherein the cancer is any type of cancer and claim 48 encompasses methods wherein the degree of 9p-arm loss is measured in any type of precancer cell.
Claim 7 recites that “loss of entire 9p arm measured as loss of ≥70% of arm.” The remaining claims encompass methods wherein 9p-arm loss is not defined. 9p-arm loss may be the loss of an one or two nucleotides within the 9p-arm or any region of the 9p-arm. For instance, claim 4 recites that measuring 9p-arm loss comprises assessing 9p21.3 loss. See also para [0116] (note that paragraph numbering herein is with respect to the published application): “Various methods can be used to assess the level of or significance of 9p-arm loss in the patient sample. In one aspect, the significance of 9-arm loss comprises assessing 9p21.3 loss. In one aspect wherein the cancer is HPV-HNSC and the significant 9p-arm loss comprises 9p21.3 loss, the assessment is associated with immune-cold tumor microenvironment (TME) signal.”
At para [0121-0135], the specification teaches that 9p-arm loss can be detected by assaying deletion of a single gene in a region of 9p.
The specification contemplates that 9p-arm loss can be indirectly measured by assessing cytokine levels or changes in signaling pathways. See, e.g., para [0133-0134]:
“9p-arm loss is assessed by measuring one or more of SASP, Cytokine-Cytokine-Receptor Interaction, JAK-STAT Signaling, and TNFA Signaling via NFkB. Alternatively or in addition, the method further comprises assessing a decrease in SASP, Cytokine-Cytokine-Receptor Interaction, JAK-STAT Signaling, and TNFA Signaling via NFkB.
9p-arm loss can also be assessed by measuring for a decrease in chemokines CXCL9 and CXCL10.”
The teachings in the specification are not commensurate with the breadth of the claims and the teachings in the specification establish the high level of unpredictability in the art of extrapolating results obtained with loss of the full length 9p-arm to loss of individual genes or regions of the 9p-arm and with extrapolating the results obtained with one type of cancer to other cancers. .
Regarding the detection of deletions of individual genes on 9p in HSCN cell lines, the specification (para [0201]) states:
“In sum, these data indicate that in cancer-cell lines, 9p-arm deletion of key immunoregulatory genes can lead to T-cell depletion observed in tumors (e.g., CCL2, CCL24). Deletion of individual regions located on 9p, such as 9p21.3 or 9p24, were not sufficient to recapitulate the effects observed in cell lines harboring deletion of the entire arm, suggesting a cumulative effect of sets of genes located on this chromosome arm.”
At para [0202], the specification teaches the results obtained in a clinical study in which PD-1 inhibitors were administered to HPV- HNSC patients having 9p loss. In this context, it appears that “9p loss” encompasses loss of the complete 9p arm. The specification states:
“These results indicated that 9p loss was a strong, specific predictive marker of clinical benefit from PD-1 inhibitors. In contrast, 3p, 17p, or 9p21.3 loss were not predictive (of anti-PD-1 therapy efficacy) (FIG. 4C), or prognostic in non-immune-checkpoint blockade (ICB) treated patients (data not shown).”
Thus, the specification teaches that in HPV- HNSC, 9p21.3 loss alone was not predictive of responsiveness to PD-1 inhibitors.
The specification teaches that in a cohort of patients treated with nivolumab or pembrolizumab, “(l)oss of 9p21 (IFNα gene set, CDKN2A deletion), 3p, and 17p were not predictive or prognostic” of clinical benefit of therapy (para [0216]).
With respect to the non-elected species, the specification teaches:
“(b)orderline predictive associations of PD-L1, -L2 and JAK2 deletion (at 9p24) were observed (data not shown), suggesting that additional gene alterations on 9p might contribute to resistance to PD-1 blockade. In regard to the strongest copy-number ICB-predictive marker in this study, patients with PD-L1-JAK2 co-deletion, had an inferior median survival vs those without this co-deletion (6 vs 19 months, p=0.007).”
The specification teaches that genes on 9p21.3 alone contribute to but are not sufficient to drive immune evasion (para [0206]). The specification (para [0206]) goes on to state:
“Without being bound by theory, Applicant's prediction-model implicates a cumulative effect of up to 40 potential candidate genes (data not shown), including CDKN2A (9p21.3), JAK2 (9p24), and several genes outside of 9p21.3 or 9p24, such as a prominent 22-gene cluster deletion in 9p13. Notable among the new candidates were RANBP6 and IL33, which can influence central processes involved in tumor microenvironment-cell recruitment and checkpoint-blockade efficacy by silencing STAT3 activity (39) and attracting immune cells to sites of tissue injury (40), respectively. A third possible culprit, TOPORS, can promote NFkB activity (41), potentially contributing to NFkB pathway suppression, T-cell depletion and escape after 9p loss.”
Thus, the teachings in the specification make clear that loss of 9p21.3 or other subregions of 9p (other than the non-elected PD-L1-JAK2 co-deletion) are not predictive of responsiveness of HPV- HNSC to PD-1 inhibitor therapy.
The specification has not established that any other subregions of 9p can be assayed for the loss of 9p sequences as predictive of response to a “PD-1/PD-L1 centered immunotherapy” in HNSC or any other cancer.
Further, the specification has not established that the findings obtained in the specification for HPV- HNSC can be predictably extrapolated to the large and diverse genus of any type of cancer, including a representative number of the hundreds of different types of cancers listed at para [0114]).
The unpredictability in the art of extrapolating the CNV results obtained with one type of cancer to other types of cancers is supported by the teachings in the specification. For instance, the specification (para [0206]) states:
“In Applicant's experiments, the IFNα-gene cluster loss (on 9p21.3), postulated to promote tumor cell-intrinsic evasion in melanoma (32), does not appear to be operative in immune-cold HNSC with 9p loss.”
The unpredictability in the art of extrapolating the results obtained with response to immunotherapy in one type of cancer to other types of cancers is supported by the teachings of Adib et al (Clinical Cancer Res. 2021. p. 1-11). Therein it is disclosed that while genetic alterations in CDKN2A in patients having urothelia carcinoma treated with immunotherapy were correlated with responsiveness to the immunotherapy, CDKN2A genomic alteration status was not correlated with responsiveness in five other cancers, including head and neck cancer, esophagogastric cancer, non-small cell lung cancer, renal cell carcinoma and melanoma (e.g., abstract; Fig. 2 and p. “OF4”, col. 2 to p. “OF5” col. 1).
The unpredictability in the art of extrapolating the results obtained with response to immunotherapy in one type of cancer to other types of cancers is also supported by the findings of Braun et al (Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma. May 2020. 26: 909-918 and Extended data, 31 pages total). In contrast to the findings in the present specification for HPV- HNSC, Braun teaches that there was a correlation between focal loss of 9p21.3 and poor response to PD-1 blockade immunotherapy and worse PFS following PD-1 blockade immunotherapy in patients having clear cell renal cell carcinoma (e.g., Fig. 6 and Extended Data Fig. 9; and p. 515, col. 2).
In view of the high level of unpredictability in the art as shown by the inability to predictably extrapolate the findings from one cancer to other cancers and to extrapolate the findings obtained with loss of the full length of the 9p-arm to individual genes and subregions of the 9p-arm, and because of the lack of specific guidance provided in the specification as to the association between deletion of subregions of 9p and response to “PD-1/PD-L1 centered immunotherapy” in a representative number of diverse cancers, it would require undue experimentation for the skilled artisan to practice the broadly claimed invention.
Case law has established that '(t)o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation.'" In re Wright 990 F.2d 1557, 1561. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) it was determined that '(t)he scope of the claims must bear a reasonable correlation to the scope of enablement provided by the specification to persons of ordinary skill in the art". The amount of guidance needed to enable the invention is related to the amount of knowledge in the art as well as the predictability in the art. Furthermore, the Court in Genetech Inc. v Novo Nordisk 42 USPQ2d 1001 held that '(I)t is the specification, not the knowledge of one skilled in the art that must supply the novel aspects of the invention in order to constitute adequate enablement".
Moreover, as set forth in Rasmusson v. SmithKline Beecham Co., 75 USPQ2d 1297, 1302 (CAFC 2005), enablement cannot be established unless one skilled in the art "would accept without question" an Applicant's statements regarding an invention, particularly in the absence of evidence regarding the effect of a claimed invention. Specifically:
"As we have explained, we have required a greater measure of proof, and for good reason. If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to "inventions" consisting of little more than respectable guesses as to the likelihood of their success. When one of the guesses later proved true, the "inventor" would be rewarded the spoils instead of the party who demonstrated that the method actually worked. That scenario is not consistent with the statutory requirement that the inventor enable an invention rather than merely proposing an unproved hypothesis."
In view of the unpredictability in the art, and the lack of disclosure and guidance provided in the specification and in the prior art, it would require undue experimentation for one of skill in the art to make and use the invention as broadly claimed.
Double Patenting
12. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-7, and 48-50 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 19/116,947(reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the present claims and the claims of ‘957 are both inclusive of methods of treating cancer in a subject in need thereof wherein a cell sample from the subject has been assayed and does not contain a 9p21.3 loss and the method comprises administering an anti-PD-1 or anti-PD-L1 treatment (i.e., immunotherapy) to the subject (see claim 1 of ‘947). The claims of ‘947 also are inclusive of methods of treating cancer in a subject in need thereof wherein a cell sample from the subject has been assayed and found to contain a 9p21.3 loss and the method comprises administering a therapy other than an anti-PD-1 or anti-PD-L1 treatment to the subject having 9p21.3 loss in the sample (see claim 9 of ‘947). Regarding claims 1-7 and 49-50, the present claims include methods wherein 9p21.3 loss is measured / has been detected in a cancer cell present in a sample from a subject, whereas the claims of ‘947 recite that 9p21.3 loss is measured in a sample comprising cells from the oral LK lesion isolated from the subject. However, oral leukoplakia, including the aggressive form of proliferative verrucous leukoplakia (claims 1 and 9), often contain cancer cells and the methods of ‘947 are directed to methods that delay oral squamous cell carcinoma, as well as methods wherein the patient has suffered from oral squamous cell carcinoma or head and neck cancer. Accordingly, it would have been obvious to one of ordinary skill in the art at the time the invention was made to have modified the method of ‘947 so as to have applied the method to lesions that contain cancer cells in order to have specifically treated subjects at risk of further progression of cancer.
Regarding present claims 5 and 6, the claims of ‘947 are inclusive of methods wherein the subject has or has suffered from oral squamous cell carcinoma or head and neck cancer (claim 11) and particularly has or has suffered from a human papilloma virus negative head and neck cancer (claim 12).
Regarding present claim 6, the limitation of “9p21.3 loss is associated with immune-cold tumor microenvironment (TME) signal” constitutes a property of 9p21.3 loss and does not distinguish the presently claimed method over that claimed in ‘947.
Regarding present claim 7, when read in light of the specification of ‘947, it is clear that loss of 9p21.3 can include loss of the entire 9p arm.
Regarding present claim 48, the claims of ‘947 encompass methods for inhibiting the growth and progression of cancer comprising measuring 9p-arm loss, including 9p21 loss in a precancer cell from the subject; determining loss of 9p21.3 loss and thereby a degree of 9p-arm loss; and administering to the subject treatment that does not comprise an anti-PD-1 therapy if there is 9p21.3 loss. Note that 9p21.3 loss is considered to be a “significant 9p-arm loss,” absent a clear definition for this phrase in the present specification.
Regarding present claims 49 and 50, claim 17 of ‘947 is inclusive of methods for predicting if a subject will respond to anti-PD-1 therapy wherein a subject not having a 9p21.3 loss in the sample is likely to respond to anti-PD-1 therapy and a patient having a 9p21.3 loss in the sample is less likely to respond to anti-PD-1 therapy as compared to a patient having the 9p21.3 loss in the sample.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
13. Claim 11 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 19/116,947(reference application) in view of Batham et al (Senescence in the Development and Response to Cancer with Immunotherapy: A Double-Edged Sword. Inter J Molec Sci. 18 June 2020, 21:4346, p. 1-31).
The claims of ‘947 are discussed above. The claims of ‘947 do not recite that the method further comprises a step of assessing SASP suppression.
However, Batham teaches that the “main role of SASP in physiological conditions is to attract immune cells to clear senescent cells avoiding tumor development…. However, in certain contexts, senescence after chemotherapy can promote cancer progression, especially when immune cells become senescent and cannot clear senescent tumor cells” (abstract).
Batham also teaches that checkpoint immunotherapies, such as monoclonal antibodies against PD-1/PD-L1 and CTLA-4, work by blocking one of the pathways that contribute to CD8+ T cell exhaustion (p. 15, final para ), thereby restoring their ability to kill target cancer cells. It is disclosed that there is some evidence that checkpoint inhibitors can increase the presence of senescent T cells and that “senescent T cells have an impaired ability to clear tumors and can even promote tumor progression” (p. 15, first para). Batham teaches that it would be advantageous in such situations to treat the patients with additional therapies that reverse T cell senescence (p. 15 to p. 16, first para).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method claimed in ‘947 so as to have included a step of assessing suppression of the SASP in order to have ensured that the anti-PD-1 therapy would be effective in treating the cancer and/or suppressing further cancer development.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
14. Claim 12 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 19/116,947(reference application) in view of Stark et al (Genome-Wide Loss of Heterozygosity and Copy Number Analysis in Melanoma Using High-Density Single-Nucleotide Polymorphism Arrays. Cancer Res. 2007. 67(6): 2632-2642).
The claims of ‘947 are discussed above. The claims of ‘947 do not recite that 9p21.3 loss is assessed by detecting deletion of the MLLT3 gene.
However, Stark teaches methods for analyzing changes in copy number in nucleic acid samples from subjects having cancer (e.g., abstract and p. 2632, col. 2 and p. 2634, col. 1). It is disclosed that the MLLT3 gene is present at 9p21.3. It is also disclosed that deletion of 9p21.3 is the most common deletion in melanoma (p. 2634, final para) and that deletion of 9p21.3 is characterized by deletion of the MLLT3 gene, (p. 2166, col. 1 and Table 4).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have specifically detected the loss of 9p21.3 by assaying for a deletion of the MLLT3 gene. One would have been motivated to have done so because Stark teaches that the MLLT3 is present in the 9p21.3 region and teaches that deletion of MLLT3 is indicative of 9p21.3 deletion. Thereby, such a modification of the method claimed in ‘947 would have provided an effective means for assessing loss of 9p21.3.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Rejections - 35 USC § 103
15. 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-7, 11, and 48-50 is/are rejected under 35 U.S.C. 103 as being unpatentable over William et al (Immune evasion in HPV− head and neck precancer–cancer transition is driven by an aneuploid switch involving chromosome 9p loss. 05 May 2021. 118(19): e2022655118, p. 1-12 and Supplementary Information, 100 pages total).
William teaches a method comprising measuring 9p-arm loss in a cancer cell from a subject, determining the degree of 9p-arm loss and determining if the subject will be responsive to treatment with an anti-PD-1 immunotherapy based on the 9p-arm loss (e.g., p. 4, col. 2 to p. 5, col. 1; “Chromosome-9p loss predicted survival of HPV− HNSC patients after immunotherapy” at p. 6 to p. 7, col. 1; and “Prediction of Survival after Cancer Immunotherapy” at p. 10). William (p. 10, col. 1) states “We identified 9p loss (Fig. 4A) as a highly specific predictive marker of anti–PD-1 clinical benefit in HPV− HNSC (P = 0.03)…. In stark contrast, 9p loss and PD-L1-JAK2 codeletion in non-ICB chemotherapy-only–treated patients lack any prognostic impact, with HRs and P values of near 1.0.” William also states (abstract): “9p arm-level loss and JAK2-PD-L1 codeletion (at 9p24) were predictive markers of poor survival in recurrent HPV− HNSC after anti–PD-1 therapy.” Similarly, William states “9p-arm loss and JAK2-PD-L1 codeletion were associated with PD-1 inhibitor resistance” (“Significance” at p. 1). In Figure 4A, it is shown that HPV- HNSC patients showing no 9p-arm loss had longer survival when treated with anti-PD-1 therapy versus patients having 9p-arm loss when treated with anti-PD-1 therapy and thereby that patients HPV- HNSC patients showing no 9p-arm loss were responsive to anti-PD-1 therapy.
Regarding claim 1, William does not exemplify as a single embodiment a method comprising administering an anti-PD-1 immunotherapy to a cancer patient if a cancer cell sample isolated from the patient does not show 9p-arm loss.
However, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have generated a method comprising administering an anti-PD-1 immunotherapy to a patient having HPV- HNSC after a cancer cell sample isolated from the patient has been assayed and found to not contain loss of the 9p-arm. One would have been motivated to have done so because William teaches that patients having HPV- HNSC and lacking a 9p-arm loss were responsive to anti-PD-1 therapy.
Regarding claim 2, William does not exemplify as a single embodiment a method comprising administering a therapy that is not a PD-1/PD-L1 centered immunotherapy to a cancer patient if a cancer cell sample isolated from the patient shows loss of the complete 9p-arm.
However, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have generated a method comprising administering a therapy that is not a PD-1/PD-L1 centered immunotherapy to a HPV (-) HSCN patient after a cancer cell sample isolated from the subject had been assayed and found to contain loss of the 9p-arm. One would have been motivated to have done so because William teaches that patients having HPV- HSCN and having loss of the 9p-arm should not be treated with a PD-L1 immunotherapy (p. 6 and figure 4A), but that some HPV (-) HNSC patients could be effectively treated with chemotherapy (e.g., Figure 4B).
Regarding claim 3, William does not specifically exemplify the administering step of claim 3.
However, William teaches methods of measuring loss of the entire 9p arm as well as methods that assay for loss of 9p21.3 (e.g., p. 4, col. 2). It is disclosed that loss of the entire 9p arm is associated with resistance to anti-PD-1 immunotherapy (abstract and “Significance” at p. 1), whereas focal loss of 9p21.3 contributed to cell-intrinsic senescence suppression (abstract) and was not predictive of responsiveness to anti-PD-1 immunotherapy (p. 7, col. 1 and Figure 4C).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have administered an anti-PD-1 immunotherapy to patients that showed only focal loss of 9p21.3 (i.e., no significant 9p-arm loss) since William teaches that anti-PD-1 immunotherapy can be effective in some patients harboring loss of only 9p23.1.
Regarding claims 4-6, as discussed above, William teaches that the patient has HPV- HNSC and teaches measuring loss of 9p21.3.
Further regarding claim 6, William teaches that 9p21.3 focal loss is associated with an immune-cold tumor microenvironment (e.g., p. 5, col. 2).
Regarding claim 7, as discussed above, William teaches methods that assay for loss of the full 9p-arm and that loss of the full 9p-arm is correlated with resistance to anti-PD-1 immunotherapy in HPV-HNSC.
Regarding claim 11, William teaches that the methods disclosed therein include further assessing cell-intrinsic senescence pathway suppression and that chromosome 9p21.3 deletion contributed mainly to this suppression (e.g., abstract).
Regarding claim 48, William does not specifically exemplify as a single embodiment the method of claim 48.
However, William teaches methods of measuring loss of the entire 9p arm as well as methods that assay for loss of 9p21.3 in precancer cells(e.g., p. 4, col. 2 and Figure 5). In the legend for Fig. 5, William states “In precancer, the dominant CN driver of immune-hot lesions was chromosome gain (trisomy, tetrasomy) and 9p21 loss” It is disclosed that “Early lesions with 9p21.3 loss were associated with depletion of cytotoxic T cell infiltration in TP53 mutant tumors; and with aneuploidy were associated with increased NK-cell infiltration” (abstract). It is also disclosed that “Chromosome 9p21.3 loss in precursor lesions, the genomic driver of malignant transition, was enhanced by cumulative 9p-arm gene-dosage decreases, cell-intrinsic senescence suppression, and extrinsic decreases in chemokine, cytokine, and NF-κB pathways. Furthermore, 9p-arm loss and JAK2-PD-L1 codeletion were associated with PD-1 inhibitor resistance” (“Significance” at p. 1)
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have administered a cancer therapy other than an anti-PD-1 immunotherapy to patients that showed a significant loss of 9p-arm chromosomal sequences in precancer cells since William teaches that anti-PD-1 immunotherapy is not effective in patients harboring a significant loss of 9p-arm sequences.
Regarding claims 49 and 50, William teaches methods of measuring 9p-arm loss in a cancer cell from a subject and determining the degree of 9p-arm loss (e.g., p. 4, col. 2 to p. 5, col. 1; “Chromosome-9p loss predicted survival of HPV- HNSC patients after immunotherapy” at p. 6 to p. 7, col. 1; and “Prediction of Survival after Cancer Immunotherapy” at p. 10).. William does not specifically recite that these steps are followed by a step of determining if a subject or if a type of cancer will respond to administering PD-1/PD-L1 centered immunotherapy if the degree of 9p-arm loss does not show significant 9p-arm loss.
However, William teaches that loss of the entire 9p-arm is correlated with resistance to anti-PD-1 immunotherapy resistance (e.g., abstract and “Significance” at p. 1; and Figure 4), whereas loss of the region of only 9p21.3 is not correlated with a poor response / resistance to anti-PD-1 immunotherapy (p. 7, col. 1 and Figure 4C)..
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of William so as to have included a step of predicting or determining that the subject will respond to anti-PD-1 immunotherapy if the degree of 9p-arm loss is not significant. One would have been motivated to have done so because William teaches that patients not having a significant loss of 9p-arm chromosomal sequences can be effectively treated with an anti-PD-1 immunotherapy.
16. Claim(s) 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over William et al in view of Stark et al (Genome-Wide Loss of Heterozygosity and Copy Number Analysis in Melanoma Using High-Density Single-Nucleotide Polymorphism Arrays. Cancer Res. 2007. 67(6): 2632-2642).
The teachings of William are presented above. William does not teach that 9p21.3 loss is assessed by detecting deletion of the MLLT3 gene.
However, Stark teaches methods for analyzing changes in copy number in nucleic acid samples from subjects having cancer (e.g., abstract and p. 2632, col. 2 and p. 2634, col. 1). It is disclosed that the MLLT3 gene is present at 9p21.3. It is also disclosed that deletion of 9p21.3 is the most common deletion in melanoma (p. 2634, final para) and that deletion of 9p21.3 is characterized by deletion of the MLLT3 gene, (p. 2166, col. 1 and Table 4).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of William by specifically detecting the loss of 9p21.3 by assaying for a deletion of the MLLT3 gene. One would have been motivated to have done so because Stark teaches that the MLLT3 is present in the 9p21.3 region and teaches that deletion of MLLT3 is indicative of 9p21.3 deletion. Thereby, such a modification of the method of William would have provided an effective means for assessing loss of 9p21.3. 17. Claim(s) 1-4, and 49-50 is/are rejected under 35 U.S.C. 103 as being unpatentable over Braun et al (Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma. May 2020. 26: 909-918 and Extended data, 31 pages total and entry #8634 in Supplementary Table 3 (shown below) available via url: < nature.com/articles/s41591-020-0839-y#Sec27>).
Note that deletion of 9p21.3 is considered to be encompassed by 9p-arm loss as recited in the presently rejected claims since the claims do not specify any particular region or percentage of loss of the 9p-arm.
Braun teaches a method comprising measuring 9p-arm loss in a cancer cell from a subject (see Methods, p. 1 of the Supplementary Information; Fig. 6 and Extended Data Fig. 9). Braun teaches that deletion of 9p21.3 is associated with a worse response to PD-1 blockade immunotherapy and worse PFS following PD-1 blockade immunotherapy (Fig. 6 and Extended Data Fig. 9). Braun also teaches that “del(9p21.3) is associated with worse OS following PD-1 blockade but not mTOR inhibition” (Fig. 6 legend). Additionally, it is stated that “We identified that CD8+ T cell infiltrated tumors are relatively depleted for PBRM1 mutations (which are associated with response19,35), and are enriched for chromosomal losses of 9p21.3 (which is associated with resistance to PD-1 blockade in infiltrated tumors)” (p. 515, col. 2). The reference shows that cancer patients lacking a 9p21.3 deletion and treated with anti-PD-1 had better overall survival (e.g., Fig. 6d) and progression-free survival (Extended Data Fig. 9c), as compared to patients having a 9p21.3 deletion (see also p. 913, col. 2).
Regarding claim 1, Braun does not exemplify as a single embodiment a method comprising administering an anti-PD-1 immunotherapy to a cancer patient if a cancer cell sample isolated from the patient does not show loss of 9p21.3.
However, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Braun so as to have administered an anti-PD-1 immunotherapy to a patient in which deletion of 9p21.3 was not detected in a cancer cell of the patient. One would have been motivated to have done so because Braun teaches that patients lacking a deletion in 9p21.3 can be effectively treated with anti-PD-1 immunotherapy.
Regarding claim 2, Braun does not exemplify as a single embodiment a method comprising administering therapy that is not a PD-1/PD-L1 centered immunotherapy to a cancer patient if a cancer cell sample isolated from the patient shows loss of the complete 9p-arm.
However, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Braun so as to have administered a mTOR inhibitor therapy (i.e., a therapy that is not a PD-1/PD-L1 centered immunotherapy) to a cancer patient if a cancer cell sample isolated from the patient shows a deletion of 9p21.3. . One would have been motivated to have done so because Braun teaches that patients having a 9p21.3 are resistant to anti-PD-1 immunotherapy, but can be effectively treated with an mTOR inhibitor (e.g., Extended Data Fig. 9c).
Regarding claim 2, William does not exemplify as a single embodiment a method comprising administering a therapy that is not a PD-1/PD-L1 centered immunotherapy to a cancer patient if a cancer cell sample isolated from the patient shows loss of the complete 9p-arm.
However, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have generated a method comprising administering a therapy that is not a PD-1/PD-L1 centered immunotherapy to a HPV (-) HSCN patient after a cancer cell sample isolated from the subject had been assayed and found to contain loss of the 9p-arm. One would have been motivated to have done so because William teaches that patients having HPV- HSCN and having loss of the 9p-arm should not be treated with a PD-L1 immunotherapy (p. 6 and figure 4A), but that some HPV (-) HNSC patients could be effectively treated with chemotherapy (e.g., Figure 4B).
Further regarding claims 3 and 4, the method of Braun is considered to be one that determines the degree of 9p-arm loss since Braun teaches assessing 9p21.3 loss (present claim 4) and teaches performing copy number analysis by detecting mutations in the region of 9p21.3 and flanking regions (see Methods at p. 1 of the Supplementary Information). Note that the claims do not recite any particular method for determining the degree of 9p-arm loss and particularly do not recite any limitations that distinguish the claimed method over that of Braun. Further, the method of Braun wherein only deletion of 9p21.3 is detected in a cancer cell from a patient is considered to be one in which the cancer cell shows significant 9p-arm loss; and absence of the 9p21.3 deletion is considered to meet the limitation of “does not show significant 9p-arm loss.” Note that there is no limiting definition in the specification for the phrase “does not show significant 9p-arm loss.”
Regarding claims 49 and 50, Braun does not specifically recite a method that determines or predicts that a subject or cancer will respond to PD-1/PD-L1 centered immunotherapy if the degree of 9p-arm loss does not show a significant 9p-arm loss.
However, as discussed above, Braun teaches that the presence of a deletion of 9p21.3 in cancer cells is predictive of a poor response to anti-PD-1 therapy and poor survival and PFS following anti-PD-1 therapy, whereas the absence of a 9p21.3 deletion (a sample or subject that does not show significant 9p-arm loss) is correlated with a better response and outcome to anti-PD-1 therapy.
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Braun so as to have included a step of predicting or determining that the subject will respond to anti-PD-1 immunotherapy if the degree of 9p-arm loss is not significant - i.e., if the subject or a cancer cell from the subject is lacking a deletion of 9p21.3. One would have been motivated to have done so because Braun teaches that patients not having a deletion of 9p21.3 shave a better response and outcome when treated with an anti-PD-1 immunotherapy.
18. Claim(s) 11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Braun et al (Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma. May 2020. 26: 909-918 and Extended data, 31 pages total and entry #8634 in Supplementary Table 3 (shown below) available via url: < nature.com/articles/s41591-020-0839-y#Sec27>) in view of Batham et al (Senescence in the Development and Response to Cancer with Immunotherapy: A Double-Edged Sword. Inter J Molec Sci. 18 June 2020, 21:4346, p. 1-31).
The teachings of Braun are presented above. Braun does not teach a method that further comprises a step of assessing SASP suppression.
However, Batham teaches that the “main role of SASP in physiological conditions is to attract immune cells to clear senescent cells avoiding tumor development…. However, in certain contexts, senescence after chemotherapy can promote cancer progression, especially when immune cells become senescent and cannot clear senescent tumor cells” (abstract).
Batham also teaches that checkpoint immunotherapies, such as monoclonal antibodies against PD-1/PD-L1 and CTLA-4, work by blocking one of the pathways that contribute to CD8+ T cell exhaustion (p. 15, final para ), thereby restoring their ability to kill target cancer cells. It is disclosed that there is some evidence that checkpoint inhibitors can increase the presence of senescent T cells and that “senescent T cells have an impaired ability to clear tumors and can even promote tumor progression” (p. 15, first para). Batham teaches that it would be advantageous in such situations to treat the patients with additional therapies that reverse T cell senescence (p. 15 to p. 16, first para).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Braun so as to have included a step of assessing suppression of the SASP in order to have ensured that the anti-PD-1 therapy would be effective in treating the cancer and/or suppressing further cancer development.
19. Claim(s) 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Braun et al (Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma. May 2020. 26: 909-918 and Extended data, 31 pages total and entry #8634 in Supplementary Table 3 (shown below) available via url: < nature.com/articles/s41591-020-0839-y#Sec27>) in view of Stark et al (Genome-Wide Loss of Heterozygosity and Copy Number Analysis in Melanoma Using High-Density Single-Nucleotide Polymorphism Arrays. Cancer Res. 2007. 67(6): 2632-2642).
The teachings of Braun et al are presented above. Braun does not teach that 9p21.3 loss is assessed by detecting deletion of the MLLT3 gene.
However, Braun does teach that the methods for assessing response of cancer patients to anti-PD-1 therapy includes assaying for mutations in the MLLT3 gene - see entry 8634 in Supplementary Table 3a:
PNG
media_image2.png
32
594
media_image2.png
Greyscale
PNG
media_image3.png
18
694
media_image3.png
Greyscale
Further, Stark teaches methods for analyzing changes in copy number in nucleic acid samples from subjects having cancer (e.g., abstract and p. 2632, col. 2 and p. 2634, col. 1). It is disclosed that the MLLT3 gene is present at 9p21.3. It is also disclosed that deletion of 9p21.3 is the most common deletion in melanoma (p. 2634, final para) and that deletion of 9p21.3 is characterized by deletion of the MLLT3 gene, (p. 2166, col. 1 and Table 4).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Braun by specifically detecting the loss of 9p21.3 by assaying for a deletion of the MLLT3 gene. One would have been motivated to have done so because Stark teaches that the MLLT3 is present in the 9p21.3 region and teaches that deletion of MLLT3 is indicative of 9p21.3 deletion. Thereby, such a modification of the method of Braun would have provided an effective means for assessing loss of 9p21.3.
20. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Mao et al (Nature Medicine. 1996. 2(6): 682-685) teaches methods of assaying oral premalignant lesions (i.e., precancerous cells) for the presence of a deletion of 9p21 (e.g., “Methods” at p. 684, col. 2 to p. 685, col. 1; and abstract). It is reported that “(t)he time to cancer development from the date of the baseline biopsy was significantly shorter in the group with 10H at 9p21 and/or 3p14 than in the group without LOH” (p. 683, col. 2). Mao concludes that “that losses of the 9p21 and 3p14 regions may be related to early processes of tumorigenesis In HNSCC.” However, Mao does not teach or suggest that 9p21 loss in oral premalignant lesions or precancerous cells is correlated with responsiveness to anti-PD-1/PD-L1 centered therapy and does not teach or suggest administering a treatment that does not comprise PD-1/PD-L1 centered immunotherapy if the degree of 9p-arm loss in an (oral) precancerous cell shows significant 9p-arm loss.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CARLA J MYERS whose telephone number is (571)272-0747. The examiner can normally be reached M-Th 6:30-5:00 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Winston Shen can be reached on 571-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/CARLA J MYERS/Primary Examiner, Art Unit 1682
Prosecution Insights