DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 December 29, 2025 has been entered.
Claim Status
The claim set and Applicant’s remarks filed on December 29, 2025 are entered.
Claims 3-5, 9-10 and 14 are canceled.
Thus, claims 1-2, 6-8, 11-13 and 15-17 as amended are examined on the merits herein.
Withdrawn Objections and Rejections
With respect to the objections and/or rejections mailed in the final office action on August 28, 2025:
(I) The objection to claims 1 and 13 is withdrawn in view of Applicant’s amendment to these claims.
(II) The rejection of claims 1-2, 4, 6-9, 11-13 and 15-17 under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendments to the claims and Applicant remarks filed December 29, 2025, which are found persuasive.
Response to Arguments
The Examiner has reviewed and considered Applicant’s claim amendments and remarks which are found persuasive to overcome the 103 rejections of record.
However, upon further consideration of Applicant’s remarks and specification, particularly Applicant’s Examples 1 and 2, see specification pp. 23-32; as well as Figures 2 and 5 filed in the Drawings on June 19, 2023, in response the Examiner has written a new 112(a)-written description rejection in view of Applicant’s claim amendments.
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 1-2, 6-8, 11-13 and 15-17 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 claims contain 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.
(A) The Examiner notes instant claims 1-2, 6-8 and 11-12 are drawn to a method of excluding the administration of a CDK4/6 inhibitor, an endocrine therapy, or a combination thereof, by determining the presence or absence of mutations in twelve genes as well as determining the luminal type obtained from a biological sample in a premenopausal subject having HR+/HER2- metastatic breast cancer, wherein said subject:
(i) has mutations limited to single nucleotide variations (SNV), insertion/deletion variations (Indel), copy number variations (CNV), deletions or inversions in one gene of the RB1 pathway, as well as mutations in BRCA2, PTEN, EPHA5, and AURKA; and (ii) CNV mutations in BRIP1 and MYC; additionally, the subject;
(iii) does not have a mutation in NOTCH4; and
(iv) has a biological sample that is characterized as a non-luminal type as the basis for the treatment selection rule to exclude said administration of a CDK4/6 inhibitor, an endocrine therapy, or a combination thereof; and consequently, administer any anticancer drug that is not a CDK4/6 inhibitor, an endocrine therapy, or a combination thereof.
(B) The Examiner notes instant claims 13 and 15-17 are drawn to a method of administering a CDK4/6 inhibitor, an endocrine therapy, or a combination thereof by determining the presence or absence of mutations in twelve genes as well as determining the luminal type obtained from a biological sample in a premenopausal subject having HR+/HER2- metastatic breast cancer, where said subject:
(i) does not have any mutations in any one gene of the RB1 pathway, or in BRCA2, PTEN, EPHA5, AURKA, MYC and BRIP1;
(ii) has either SNV, Indel, CNV, deletions or inversions in NOTCH4; and
(iii) has a biological sample that is characterized as a luminal type as the basis for the treatment selection rule to administer a CDK4/6 inhibitor, an endocrine therapy, or a combination thereof to the subject.
Accordingly, MPEP 2163(I)(B) states “The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, the inventor was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117”.
Consequently, the instant claims have been analyzed in accordance with the methodology for determining adequacy of written description, see MPEP 2163(II):
1. For each claim, determine what the claim as a whole covers, e.g. the first step is to determine what the claim as a whole covers, i.e., discussion of the full scope of the claim.
(I) Claim 1 and dependent claims therefrom are drawn to a method of treating HR+/HER2- metastatic breast cancer in a premenopausal subject, the method consisting essentially of:
Detecting in a biological sample of the subject, the presence or absence of mutations in each of the following biomarkers:
i) one or more genes selected from TP53, ATM, RB1, CDK4 and CHEK1 (i.e. these genes make up the RB1 pathway); as well as
ii) NOTCH4;
iii) BRCA2;
iv) PTEN;
v) EPHA5;
vi) BRIP1;
vii) AURKA; and
viii) MYC; and determining a luminal type of the subject.
The Examiner notes claim 1 limits the mutation type for this patient population to copy number variations (CNV) for the BRIP1 and MYC genes; and single nucleotide variations (SNV), insertion/deletion variation (Indel), CNV, deletion, and inversion for all remaining genes (one selected from TP53, ATM, RB1, CDK4, CHEK1; as well as NOTCH4, BRCA2, PTEN, EPHA5 and AURKA).
The Examiner further notes after the detecting step as discussed above, it is determined the subject has mutations in at least one gene of the RB1 pathway, and in BRCA2, PTEN, EPHA5, BRIP1, AURKA, and MYC; does not have a mutation in NOTCH4 and has a non-luminal type.
Consequently, the Examiner notes based on the detected mutational gene status and luminal type of the subject above, the subject is not administered a first anti-cancer drug, wherein said first anti-cancer drug is a CDK4/6 inhibitor, an endocrine therapy agent, or a combination thereof; and as a result is administered a second anticancer drug which the Examiner reasonably interprets as any anticancer drug that is not a CDK4/6 inhibitor, an endocrine therapy, or a combination thereof.
(II) Claim 13 is drawn to a method of treating HR+/HER2- metastatic breast cancer in the same patient population by detecting the same mutations in the same genes and determining the luminal type of the subject.
The substantive difference is claim 13 requires a different mutational gene status and luminal type within the subject to administer the first anti-cancer drug discussed above; wherein the subject is determined not have a mutation in at least one gene of the RB1 pathway, or in BRCA2, PTEN, EPHA5, BRIP1, AURKA, and MYC; does have a mutation in NOTCH4; and has a luminal type.
2. Review the entire application to understand how Applicant provides support for the claimed invention including each element and/or step, e.g. the second step is to fully review the application to understand how Applicant provides support for the claimed invention including each element and/or step, i.e., compare the scope of the claim(s) with the scope of the description.
The Examiner notes Applicant allegedly provides written description support for the invention now claimed in Applicant’s Examples 1 and 2, see specification pp. 23-32; as well as Figures 2 and 5.
However, the Examiner notes the examples and figures as discussed above do not provide written description support for the method of claim 1 or claim 13 as now claimed as discussed in greater detail below.
3. Determine whether there is sufficient written description to inform a skilled artisan the Inventor was in possession of the claimed Invention as a whole at the time the application was filed, e.g. the third step is to determine whether the Applicant was in possession of the claimed invention as a whole at the time of filing.
This should include the following considerations: (1) actual reduction to practice, (2) disclosure of drawings or structural chemical formulas, (3) sufficient relevant identifying characteristics such as complete structure, partial structure, physical and/or chemical properties and functional characteristics when coupled with a known or disclosed correlation between function and structure, (4) method of making the claimed invention, (5) level of skill and knowledge in the art and (6) predictability of the art.
The preceding six considerations have been considered, with the most relevant factors discussed below.
Actual Reduction to Practice:
For claims 1-2, 6-8, 11-13 and 15-17, Applicants disclose Examples 1 and 2, as well as Figures 2 and 5.
Firstly, Example 1 of the specification (see pp. 24-29) discloses a process from which the Inventor’s selected the biomarker genes now recited as being associated with drug therapeutic response and prognosis in premenopausal subjects having HR+/HER2- metastatic breast cancer.
The inventors conducted next generation sequencing (NGS DNA/RNA) of patients who were treated with a combination consisting of palbociclib (e.g. a CDK4/6 inhibitor) and exemestane (e.g. an endocrine therapy), palbociclib and exemestane will hereafter collectively be referred to as “the drug”, and wherein specific gene mutations associated with survival of breast cancer patients after said NGS were identified.
Inventors further developed a model constructed from survival analysis after combining the follow-up survival data of the patients who received the drug with the NGS results.
The model was constructed from a cohort of 141 premenopausal HR+/HER2- metastatic breast cancer patients where a tumor sample was isolated from a group (n=62) administered the drug and where sequencing was performed on said sample.
The samples were scanned with the CANCERSCANTM panel comprising 375 detectable cancer-related gene variations, where transcriptome analysis was performed to detect overall gene expression patterns, and wherein the genomic differences related to drug response in progression-free survival (PFS) in patients with poor prognosis and patients with good prognosis using said gene variation and gene expression were examined.
Inventors performed a univariate Cox proportional hazard model analysis to analyze each genetic variation/CNV where 47 biomarkers with a p-value < 0.05 (the criterion for a statistically significant difference) were selected as biomarker candidates.
The biomarker genes AURKA and MYC were selected as biomarkers through the stepwise variable selection process of multivariate Cox proportional hazard model analysis; and through this process further identified that a molecular subtype of breast cancer, e.g. a luminal type, when combined with AURKA and MYC was a significant biomarker. The Examiner respectfully notes the three-biomarker combination (i.e. AURKA, MYC and a luminal type) corresponds to model 1 in paragraph #4 of pg. 2 within the Park declaration filed April 28, 2025; and corresponds to model 10 in Table 4 of Example 1 on pg. 30 of the specification.
Moreover, in addition to the three-biomarker combination as discussed above (i.e. AURKA, MYC and a luminal type), the inventors included 10 additional genes which include: TP53, ATM, RB1, CDK4, CHEK1 (e.g. genes of the RB1 pathway as claimed above), NOTCH4, BRCA2, PTEN, EPHA5, and BRIP1 allegedly to more accurately predicted therapeutic response and prognosis of an anticancer drug (e.g. any anticancer drug). Inventors considered the genes of the RB1 pathway as one biomarker due to the small number of mutations within these genes. See specification, pg. 26, lines 5-10.
Consequently, the Examiner notes the 10 additional genes resulted in the inclusion of 6 additional biomarker candidates for Cox proportional hazard model analysis; and when combined with the three previous biomarkers, resulted in a nine-biomarker panel corresponding to the nine biomarkers recited in the methods of independent claim 1 and independent claim 13.
The Examiner also notes Fig. 2 shows the results of the multivariate Cox proportional model analysis integrating the nine types of biomarkers as discussed above, and where Applicant concludes based on the performance of this statistical model the prognosis was poor for young premenopausal patients who did not have a mutation in NOTCH4, had a mutation in one gene from the RB1 pathway, as well as in BRCA2, BRIP1, EPHA5, PTEN, AURKA and MYC, as well as a non-luminal type (see specification, pg. 26, paragraph [0095]).
Inventors also disclose these biomarker genes and molecular subtype (e.g. luminal vs. non-luminal) were significantly associated with progression-free survival (PFS) to palbociclib and exemestane in the HR+/HER2- premenopausal metastatic breast cancer (MBC) patient test group (see specification, pg. 27, paragraph [0096]).
The Examiner also notes within Example 1 the frequency of gene mutations within the biomarker genes tested within the HR+/HER2- premenopausal MBC patient test group were examined as compared to the frequency of mutations within these tested biomarker genes within the normal population as shown in Table 1 (see specification, pg. 27, paragraph [0098], Table 1); wherein Table 1 depicts the normal population does not possess mutations within any of the biomarker genes selected in Fig. 2 and corresponds to the twelve genes of the nine-biomarker panel as discussed above (see pg. 27, paragraph [0099]).
Secondly, Example 2 provides a statistical analysis of the nine-biomarker panel as discussed in Example 1, where said nine-biomarker panel corresponds to the last biomarker panel in Table 4 (see specification, pg. 30, paragraph [00105], Table 4); and corresponds to model 6 of the Park declaration filed April 28, 2025 on pg. 2, paragraph #4.
Applicant previously declared model 6 to be a statistically significant biomarker panel based on the multivariate Cox proportional hazard model which determined its C-index was 0.841 (see Park declaration filed April 28, 2025, pg. 1, paragraph 3); and where based on the general guidance of the specification which disclosed C-index values greater than 0.7 demonstrate an acceptable performance of the predictive model (see specification, pg. 30, paragraph [00104]); Applicant declared the nine-biomarker panel demonstrated significantly enhanced predictive performance within the HR+/HER2- premenopausal metastatic breast cancer (MBC) test group (see Park declaration filed April 28, 2025, pg. 2, paragraph #6).
The Examiner also notes Fig. 5 shows prognosis of the premenopausal HR+/HER2- MBC patients when the nine-type biomarker combination (i.e. the 12 genes and luminal type as discussed above) as presently claimed in claims 1 and 13 is combined with patient survival data of the 141-patient cohort discussed above.
The Examiner notes the specification describes two groups within Fig. 5, (i) the mutation (MUT) group which are premenopausal HR+/HER2- MBC patients who are determined to have a normal NOTCH4 gene (e.g. no mutation); a non-luminal molecular subtype, and have a mutation in any of the other 11 genes; where the progression free survival of these patients were compared to the wild-type (WT) group who were patients in which the NOTCH4 gene had a mutation, were a luminal molecular subtype, and where all other genes were normal (e.g. did not have a mutation); the inventors had concluded based on the combination of the presently claimed nine-biomarker panel when coupled with the survival data of the premenopausal HR+/HER2- MBC patients suggested the MUT group had relatively poor prognosis at about 3.3 times higher than the WT group (see specification, pg. 32, paragraph [00110]).
Consequently, the inventors state in view of the above examples and analysis it was possible to predict the therapeutic response and prognosis of premenopausal HR+/HER2- metastatic breast cancer using the selected nine-biomarker set as presently recited in claims 1 and 13 to select a therapeutic method for the recited patient population in claims 1 and 13 (see specification, pg. 32, paragraph [00111]).
Sufficient Relevant Identifying Characteristics:
Although the Examiner acknowledges Examples 1 and 2 provided by Applicant, the Examiner notes each example is not a reduction to practice; as Applicant’s Examples 1 and 2 only provide a statistical argument for the nine-biomarker set as presently claimed within claims 1 and 13.
Additionally, although Fig. 5 describes the MUT group which captured 57 out of the 141 premenopausal patients having HR+/HER2- MBC where palbociclib (e.g. a CDK4/6 inhibitor) and exemestane (e.g. an endocrine therapy) were previously administered as an anticancer therapy, the Examiner notes the specification describes the MUT group as including detecting any mutation in the other 11 genes which the Examiner notes conflicts with the recitation in independent claim 1 which recites excluding the administration of said CDK4/6 inhibitor and endocrine therapy combination to premenopausal HR+/HER2- MBC subjects because the subject has mutations in all biomarker genes recited expect for NOTCH4.
Accordingly, the Examiner notes Applicant’s Fig. 5 which discusses the relatively poor prognosis of the MUT group as compared to the WT group does not provide a working example or support for the mutational status of the biomarker genes recited in claim 1, lines 21-24 for use in the treatment method claimed, because the biomarkers used in Fig. 5 do not provide information of a therapeutic outcome within the examined patient population of claim 1 as Fig. 5 does not test, examine, or analysis the therapeutic outcome of the now claimed patient population who are required to have mutations in all biomarker genes as recited in claim 1 as justification for not administering the combination of a CDK4/6 inhibitor and endocrine therapy to said patient population.
Additionally, the Examiner notes Applicant’s Fig. 5 shows all 22 out of the 141 patients described as the WT group as discussed above have 100% progression-free survival (PFS) at 6 months, however, by 12 months the WT group and the MUT group have a similar decrease in PFS, 27% as compared to 36% respectively.
Consequently, although Applicant’s statistical model analysis as discussed above may suggest the statistical acceptability of the recited nine-biomarker panel, in view of the actual therapeutic and prognostic response when using the described nine-biomarker panel in Example 2 as described above, the specification does not seem to provide written description support for the nine-biomarker panel as recited in in the methods of independent claim 1 and independent claim 13.
Furthermore, the Examiner notes Applicant does not test the recited mutational gene status in the recited patient population as required in either claim 1 or claim 13 and is particularly noteworthy as the nine-biomarker panel used to determine the mutational gene status of the subject in claim 1 or claim 13 is further used as the basis for the treatment selection rule to either exclude or include the administration of a CDK4/6 inhibitor, an endocrine therapy or a combination thereof to the recited patient population.
Rather, it seems in view of the foregoing reasons above, Applicant uses the previously discussed Cox statistical analysis of the recited nine-biomarker panel and the frequency of mutations of said genes within the nine-biomarker panel as justification to extrapolate the recited nine-biomarker panel has predictive therapeutic and prognostic value when comparing the 141 premenopausal HR+/HER2- MBC subjects of Examples 1 and 2 in view of the mutational status of the wild-type population.
Level of Skill and Knowledge in the Art: The level of skill in the art is high, about that of a Ph.D. scientist with several years of experience.
Consequently, having analyzed the claims with regard to the written description guidelines as discussed above, it is clear that the specification does not provide written description support to treat HR+/HER2- metastatic breast cancer in premenopausal subjects by excluding treatment with a CDK4/6 inhibitor, an endocrine therapy or a combination thereof based on the mutational status of the 12 genes and non-luminal molecular subtype of the subject recited in claim 1, lines 21-24, because Applicant does not provide support with data from said patients having said recited mutational gene status and non-luminal type as required in claim 1.
Moreover, Applicant does not provide support with data to administer said CDK4/6 inhibitor, endocrine therapy or combination thereof because of the mutation status of the 12 genes and luminal subtype recited in claim 13, pg. 4, lines 13-17.
Thus, one skilled in the art would reasonably be lead to conclude that Applicant was not in possession of the claimed invention at the time the application was filed.
Conclusion
No claims are allowed in this action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARET J CREWS whose telephone number is (571)270-0962. The examiner can normally be reached Monday-Friday: 9:00am-5:30pm 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, Renee Claytor can be reached at (571) 272-8394. 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.
/JARET J CREWS/Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691
Prosecution Insights