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 .
Claim Status
Claims 1, 2, 6, 7, 16-19, 21-23, and 25-34 are under examination. No other claims are currently pending in the present application.
Priority
The present application was filed on April 20, 2023 and is a 371 of PCT/US2021/055810, filed on October 20, 2021, which claims the benefit of U.S. Provisional Application No. 63/094,574, filed on October 21, 2020.
Information Disclosure Statement
The references cited in the PCT international search report by the US ISA (issued February 1, 2022) have been considered, but will not be listed on any patent resulting from this application because they were not provided on a separate list in compliance with 37 CFR 1.98(a)(1). In order to have the references printed on such resulting patent, a separate listing, preferably on a PTO/SB/08 form, must be filed within the set period for reply to this Office action.
It is noted that no Information Disclosure Statement has been filed in the present application.
Claim Rejections - 35 USC § 112
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.
Claims 1, 2, 6, 7, 16-19, 21-23, and 25-34 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
The terms “high” and/or “low” in claims 1, 2, 6, 7, 16-18, 25, 27, 28, and 31 are relative terms which renders the claims indefinite. The terms are not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
While claims 16-18 and 25-31 recite defining high and low levels by comparison to various controls (claims 16-18) and by various methods (claims 25-31), neither the claims nor the specification provides a standard for ascertaining the requisite degree of “high” or “low” expression. It is unclear whether the relative terms simply require that the measured PDGFRb expression level is greater or less than one of the recited alternative controls (i.e. 1.001 vs 1.0) or whether there is some threshold (i.e. at least 10% higher, 2x higher, etc.) that is required for a particular sample to be considered as having meaningfully higher or lower expression of PDGFRb than the control(s).
Similarly, claims 7 and 34 recite the relative term “more aggressive” to modify “an invasive breast cancer” without defining what features would define a particular invasive breast cancer as being “more aggressive” than another (i.e. expression of various proteases, loss of adhesion molecules, EMT-phenotypic markers, vascularization, spread to local lymph nodes, or some other feature(s)).
Similarly, claim 21 recites the term “more intense” to modify a “level of therapy” without defining what factors define the intensity of a particular therapy (i.e. side effects experienced by subjects, number of drugs in a particular combination therapy, number of different interventions (i.e. surgery and/or radiation and/or chemotherapy and/or immunotherapy, or something else).
Claims 16-19, 21-23, and 25-34 are also indefinite as including the indefinite limitations of the claim(s) upon which they depend.
Claim 7 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 7 recites “traditional breast cancer therapy”. The term “traditional” renders the claim indefinite because “traditional” methods are subject to constant change.
Claims 19, 21, and 34 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claims 19, 21, and 34 contain the trademark/trade name “NCCN” and “NCCN Guidelines”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b). See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe the guidance issued by the corporation “National Comprehensive Cancer Network, Inc.” and, accordingly, the identification/description is indefinite.
Furthermore, reference to the guidelines issued by an organization do not reasonably apprise the ordinary artisan of the metes and bounds of the claim because said guidelines are subject to change. Indeed, if the claimed method were to be adopted into the NCCN guidelines for treatment of a subset of breast cancers as claimed, then the recited limitations of claims 19, 21, and 34 requiring therapies that are “more aggressive”, “more intense”, “alternative” to, or “at least more than” what would be recommended by the NCCN would become meaningless. Likewise, if the referenced guidelines were to be changed to eliminate or add aspects of the recommended treatment regime, then the claim language would become broader or narrower with time. Therefore, the ordinary artisan would not be reasonably apprised of the metes and bounds of the claims based upon the present claim language.
Claim 1 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 1 recites alternative steps of treating a subject conditional upon a level of stromal and/or epithelial PDGFRb comprising: a) treating with radiotherapy if the level of PDGFRb is low and b) treating with an alternative to standard radiotherapy if the level of PDGFRb is high.
These limitations render the claim indefinite because “treating the subject with radiotherapy” encompasses all possible types of treatment with radiotherapy (i.e. any dose in any number of fractions), while “an alternative to standard radiotherapy” encompasses, as made explicit by claim 22, methods comprising only administration of radiotherapy of intensities (presumably) not commensurate with “standard” methods of treatment. Therefore, the recitation of “treating with an alternative to standard radiotherapy” encompasses “treating with radiotherapy” and the claimed method therefore encompasses treating subjects with the same radiotherapy regardless of the PDGFRb expression level.
Claim 27 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 27 defines “high” PDGFRb expression as “PDGFRb levels as the highest 10% of a population of PDGFRb levels of a population of people”. It is unclear to what population the claim refers. “a population of people” may be interpreted as encompassing at least any of the following alternatives: one embodiment of the specification “SweBCG91RT”, all invasive breast cancer patients, invasive breast cancer patients in a particular national/demographic/geographical group, all breast cancer patients, all cancer patients, a representative sample of a particular national/demographic/geographical group matched to the invasive breast cancer patients in question, or all people.
Applicant is reminded that no new matter may be added to the disclosure.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 2, 6-7, 16-19, 25, 28, 30, and 32-34 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Strell et al., “Impact of Epithelial-Stromal Interactions on Peritumoral Fibroblasts in Ductal Carcinoma in Situ” JNCI J Natl Cancer Inst (2019) 111(9):djy234 pages 983-995 (published February 28, 2019) as evidenced by Gradishar et al., “Breast Cancer, Version 3.2020”, JNCCN-Journal of the National Comprehensive Cancer Network Volume 18, Issue 4 April 2020.
It is noted that Strell et al. has inventors who are inventors on the present application. However, this document was published more than one year prior to the earliest filing date of the present application (October 21, 2020). Therefore, this document qualifies as prior art under 102(a)(1) and the 102(b)(1) exceptions do not apply.
Regarding claims 1-2, 6-7, and 34 Strell et al. teach high PDGFRb expression in stroma and/or epithelia in invasive breast cancer is associated with poor prognosis including increased risk for recurrence (Strell et al., page 983, abstract) after treatment comprising breast conserving surgery, radiotherapy, and or hormonal treatment (Strell et al., page 983, column 1-column 2 bridging paragraph). Strell et al. teach treating subjects with high PDGFRb expression with alternatives to standard therapy comprising radiotherapy and standard therapy comprising radiotherapy for subjects without the high PDGFRb expression signature (Strell et al., page 983).
Regarding claims 16-17, Strell et al. define PDGFRb expression levels by comparison to control samples of normal, cancer-free breast tissue (i.e. from a healthy subject or from a tissue that does not include invasive breast cancer (Strell et al., page 984, column 1, paragraph 6).
Regarding claim 18, Strell et al. teach normalizing (i.e. comparing) PDGFRb expression levels to the level of expression of Beta-Actin (i.e. a house keeping gene) (Strell et al., Figure 3 caption) or “GAPDH as housekeeping gene” (Strell et al., Figure 4 caption).
Regarding claim 19, the standard therapies taught by Strell comprising breast conserving surgery, radiotherapy, and or hormonal treatment (Strell et al., page 983, column 1-column 2 bridging paragraph) are therapies in line with the guidelines in the NCCN guidelines at the time of filing (as evidenced by Gradishar et al., whole document, which are/were said guidelines for breast cancer and comprise guidelines for “recurrent/stage IV breast cancer” (i.e. recurrent, invasive breast cancer)) at the time of publication of Gradishar et al. in April 2020.
Regarding claim 25 and 28, Strell et al. teach measuring PDGFRb expression levels by intensity of stroma staining and percent of positive fraction of the tumor stained (Strell et al., figure 1A).
Regarding claim 30, Strell et al. teach analyzing PDGFRb expression as a continuous variable (i.e. metric) in calculating a continuous risk assessment (Strell et al. page 984, column 2, paragraph 4-5).
Regarding claims 32-33, Strell et al. teach analyzing PDGFRb expression in the stroma and epithelia (Strell et al., page 984, column 2, paragraph 6-page 985, paragraph 5).
Claims 1, 2, 6-7, and 22-23 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Weigel et al., “In vitro effects of imatinib mesylate on radiosensitivity and chemosensitivity of breast cancer cells” BMC Cancer 2010, 10:412.
Regarding claims 1, 2, and 6-7, Weigel et al. teach methods of treating subjects with invasive breast cancer wherein a level of active (phosphorylated) PDGFRb is high in the subject (Weigel et al., abstract). Weigel et al. teach methods of treating said subjects with standard radiotherapy combined with imatinib (Weigel et al., abstract) (i.e. an alternative/ a more “aggressive therapy” to standard radiotherapy). Weigel et al., further teach that imatinib is an inhibitor of PDGFRb activation that increases the efficacy of standard chemotherapy and radiotherapy (Weigel et al., page 2, column 1). Finally, Weigel et al. teach that PDGFRb expression is prognostic in peritumoral stroma in metastatic (i.e. invasive) breast cancers (Weigel et al., page 10, column 1, paragraph 1).
Regarding claim 22, Weigel et al. teach radiotherapy comprises applying 50 Gy total in 1.8-2 Gy fractions (i.e. more than (40, 42.5, or 26 Gy total)).
Regarding claim 23, Weigel et al. teach applying radiotherapy in combination with imatinib (i.e. a tyrosine kinase inhibitor against PDGFRb) (Weigel et al., page 12, column 2).
Claims 1 and 6-7 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zannetti et al., “PDGFRb as a new biomarker for metastatic triple-negative breast cancer: development of a theranostic anti-PDGFRb Aptamer for imaging and suppression of metastases” ESMO Open2018; 3(Suppl 2):A1-A463, P0-038.
Regarding claims 1, and 6-7, Zannetti et al. teach methods for treating subjects with triple negative breast cancer (i.e. invasive/aggressive breast cancer), wherein high PDGFRb expression is associated with higher metastatic behavior. Zannetti et al. further teach treating the subject with high PDGFRb with Gint4.T-NIR (an RNA aptamer that suppresses growth of metastases, cell migration, and invasion; i.e. an alternative to standard radiotherapy) (Zannetti et al., full abstract).
Claim Rejections - 35 USC § 103
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.
Claims 1, 2, 6, 7, 16-19, 21-23, and 25-34 are rejected under 35 U.S.C. 103 as being unpatentable over Strell et al., “Impact of Epithelial-Stromal Interactions on Peritumoral Fibroblasts in Ductal Carcinoma in Situ” JNCI J Natl Cancer Inst (2019) 111(9):djy234 pages 983-995 (published February 28, 2019) as evidenced by Gradishar et al., “Breast Cancer, Version 3.2020”, JNCCN-Journal of the National Comprehensive Cancer Network Volume 18, Issue 4 April 2020 in view of Weigel et al., “In vitro effects of imatinib mesylate on radiosensitivity and chemosensitivity of breast cancer cells” BMC Cancer 2010, 10:412 and Pasquier et al., “Intensity-modulated radiation therapy with simultaneous integrated boost for locally advanced breast cancer: a prospective study on toxicity and quality of life” Scientific Reports (2019) 9:2759, published February 26, 2019.
Regarding claims 1-2, 6-7, and 34, Strell et al. teach high PDGFRb expression in stroma and/or epithelia in invasive breast cancer is associated with poor prognosis including increased risk for recurrence (Strell et al., page 983, abstract) after treatment comprising breast conserving surgery, radiotherapy, and or hormonal treatment (Strell et al., page 983, column 1-column 2 bridging paragraph). Strell et al. teach treating subjects with high PDGFRb expression with alternatives to standard therapy comprising radiotherapy, breast conserving therapy, and or hormonal treatment and standard therapy comprising radiotherapy for subjects without the high PDGFRb expression signature (Strell et al., page 983).
Regarding claims 16-17, Strell et al. define PDGFRb expression levels by comparison to control samples of normal, cancer-free breast tissue (i.e. from a healthy subject or from a tissue that does not include invasive breast cancer (Strell et al., page 984, column 1, paragraph 6).
Regarding claim 18, Strell et al. teach normalizing (i.e. comparing) PDGFRb expression levels to the level of expression of Beta-Actin (i.e. a house keeping gene) (Strell et al., Figure 3 caption) or “GAPDH as housekeeping gene” (Strell et al., Figure 4 caption).
Regarding claim 19, the standard therapies taught by Strell comprising breast conserving surgery, radiotherapy, and or hormonal treatment (Strell et al., page 983, column 1-column 2 bridging paragraph) are therapies in line with the guidelines in the NCCN guidelines at the time of filing (as evidenced by Gradishar et al., whole document, which are said guidelines for breast cancer and comprise guidelines for “recurrent/stage IV breast cancer” (i.e. recurrent, invasive breast cancer)).
Regarding claims 21-23, Strell et al. teach treating subjects with high PDGFRb expression with alternatives to standard therapy comprising radiotherapy, breast conserving therapy, and or hormonal treatment and standard therapy comprising radiotherapy for subjects without the high PDGFRb expression signature (Strell et al., page 983). Strell et al. further teach PDGFRb overexpression/activation by notch-signaling is a biomarker associated with poor-prognosis given standard treatments. Strell et al. do not teach treating high PDGFRb-expressing breast cancers with “more intense” levels of therapy than that outlined in the “NCCN Guidelines” comprises the specific radiation dosing regimens recited by claim 22 or the specific combination therapies recited by claim 23.
However, Weigel et al. teach methods of treating subjects with invasive breast cancer wherein a level of active (phosphorylated) PDGFRb is high in the subject (Weigel et al., abstract). Weigel et al. teach methods of treating said subjects with radiotherapy comprising 50 Gy combined with imatinib (Weigel et al., abstract) (i.e. an alternative/ a more “aggressive therapy” to standard radiotherapy). Weigel et al., further teach that imatinib is an inhibitor of PDGFRb activation that increases the efficacy of standard chemotherapy and radiotherapy (Weigel et al., page 2, column 1). Finally, Weigel et al. teach that PDGFRb expression is prognostic in peritumoral stroma in metastatic (i.e. invasive) breast cancers (Weigel et al., page 10, column 1, paragraph 1).
Similarly, Pasquier et al. teach reduced rates of reoccurrence and mortality in locally advanced breast cancer after treatment with surgical intervention and boosted “standard radiotherapy” (Pasquier et al., abstract) comprising radiation doses of 50 Gy (25 fractions of 2 Gy each with simultaneous integrated boost of 60 Gy in 25 fractions of 2.4 Gy each (Pasquier et al., page 2, paragraph 7).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have modified the standard treatments for breast cancer irrespective of PDGFRb status taught by Strell et al. and Gradishar et al. with the teachings of Weigel et al. comprising combining radiotherapy with imatinib (i.e. a PDGFRb inhibitor) treatment for patients with high tumor PDGFRb activity and the teachings of Pasquier et al. that intensified radiotherapy improves recurrence and mortality rates in breast cancer.
The ordinary artisan would have been motivated to modify the methods of Strell et al. comprising PDGFRb testing with the teachings of Weigel et al. comprising combination breast cancer therapy with radiation and imatinib and the teachings of Pasquier et al. comprising higher “boost” doses of radiation in breast cancer by the teachings of Weigel et al. that PDGFRb inhibitor treatment increases chemosensitivity of breast cancer cells expressing high levels of activated PDGFRb (Weigel et al., abstract). The ordinary artisan would therefore have had a reasonable expectation that the combination therapy (radiation and imatinib) taught by Weigel et al. would have further increased the efficacy of the radiation-boosted therapies taught by Pasquier et al. in patients exhibiting the prognostic marker (high expression of activated PDGFRb) taught by Weigel et al. and Strell et al. relative to the “standard” therapies taught by Gradishar et al.
Regarding claim 25 and 28, Strell et al. teach measuring PDGFRb expression levels by intensity of stroma staining and percent of positive fraction of the tumor stained (Strell et al., figure 1A)
Regarding claims 26, 27, 29, and 31, the “wherein” clauses defining alternative definitions of “high” and “low” PDGFRb expression consisting of: defining expression levels into tertiles or quintiles, defining “high” expression as among the top 10% of expression levels in an (undefined) population of people, defining “high or low” levels as a function of a fraction of stromal staining and expression levels by multiplying the fraction by the expression levels, or defining “high” or “low” expression only in the area of the tumor with the highest PDGFRb stromal expression, respectively, do not recite active method steps that further limit the claimed methods. Rather, these claims consist of alternative stated definitions for “high” or “low” expression of PDGFRb. Furthermore, each of these criteria for defining relative expression of particular genes (dividing expression levels into quantiles, comparing expression levels in a sub-population of interest to a larger population, integrating “staining” and “expression” measures, and selecting a region of cells of interest in a larger sample are each well-known in the art and would have been obvious alternative definitions of “high” and “low” expression of any particular gene product of interest to those having ordinary skill in the art.
Regarding claim 30, Strell et al. teach analyzing PDGFRb expression as a continuous variable (i.e. metric) in calculating a continuous risk assessment (Strell et al. page 984, column 2, paragraph 4-5).
Regarding claims 32-33, Strell et al. teach analyzing PDGFRb expression in the stroma and epithelia (Strell et al., page 984, column 2, paragraph 6-page 985, paragraph 5).
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY MARK TURPIN whose telephone number is (703)756-5917. The examiner can normally be reached Monday-Friday 8:00 am - 5:00 pm.
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/Z.M.T./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682