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 .
The examiner reviewing this application in the USPTO have changed. All new correspondence should be directed to examiner Bailey Buchanan, Art Unit 1682.
Election/Restrictions
Applicant's election with traverse of the claims of Group I, claims 1-9, 12, & 14, and the species election of the single combination of three genes MLH1, KLK3, and HOXB13 and of prostate-specific antigen (PSA) in claim 5 in the reply filed on 06/01/2026 is acknowledged. In addition, the addition of new claims 15 & 16 in the reply filed 06/01/2026 is acknowledged. The traversal is on the ground(s) that Group I (method) and Group II (computer program) are so linked as to form a single general inventive concept under 37 CFR §1.475 as the computer program of claim 10 comprises instructions that, when executed, cause the computer to carry out the method of Group I and thus they share a corresponding technical feature of a gene-expression-based prediction of radiotherapy response. The traversal is also on the grounds that the species of genes and clinical parameters are obvious variants of the generic invention and are linked by the common technical concept of predicting radiotherapy response in a prostate cancer subject based on a gene expression profile under a PDE4D7 knockdown model. This is not found persuasive because the method and the computer program lack unity of invention since the method does not recite or require the computer program and therefore they do not share a special technical feature. Further, the only aspect the species have in common is that they are different methods for predicting response to salvage radiotherapy based on the expression of genes, however there is not a common set of genes required by all species that can be considered a special technical feature and the species lack unity of invention because they lack the same or corresponding special technical feature since they are directed to structurally and functionally different nucleic acid genes and mechanisms of clinical parameters. Further, Zhao et al. (Lacet Oncol 2016; 17: 1612-20) teaches a common technical feature of genes that are associated with predicting response to salvage radiotherapy.
The requirement is still deemed proper and is therefore made FINAL.
A first office action on the merits of Group I claims 1, 3-9, 12, & 14-16 with the species elections of the single combination of three genes MLH1, KLK3, and HOXB13 and of prostate-specific antigen (PSA) is set forth herein. Group II, claim 10, and claim 2 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable or generic linking claim.
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3-9, 12, & 14-16 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.
Regarding claim 1, the recitation of “CDK12, FANCA, MRE11 and PALB2” in lines 6-7 of the claim is unclear if MRE11 and PALB2 are part of the same group of genes or if this is the result of a typographical error and should read “CDK12, FANCA, MRE11, and PALB2”. In addition, the claim recites the limitations “the prediction” and “the radiotherapy response” in line 9 of the claim and there is insufficient antecedent basis for this limitation in the claim. In addition, the recitation of “determining the prediction of the radiotherapy response based on the gene expression levels for three of more genes” in lines 9-10 of the claim is unclear what the relationship is between the prediction of radiotherapy response and the expression levels of three or more genes. Does increased or decreased expression indicate a particular prediction of radiotherapy response? How does the expression level of three or more target genes relate back to prediction of radiotherapy response and how does difference in expression levels of the three or more genes favor a particular prediction for radiotherapy response?
Regarding claim 3, the claim recites the limitation “the therapy response” in line 2 of the claim and there is insufficient antecedent basis for this limitation in the claim and it is unclear if “the therapy response” is meant to refer back to “the radiotherapy response” as recited in claim 1, from which claim 3 depends from.
Regarding claim 4, the recitation of “determining of the prediction of the radiotherapy response is further based on one or more clinical parameters obtained from the subject” in lines 1-3 of the claim is unclear what the relationship is between the prediction of radiotherapy response and one or more clinical parameters. How does one or more clinical parameters relate back to prediction of radiotherapy response and how does difference in one or more clinical parameters favor a particular prediction for radiotherapy response?
Regarding claim 5, the phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 7, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention.
Regarding claim 8, the claim recites the limitation “the prediction” in lines 2 & 3 of the claim and there is insufficient antecedent basis for this limitation in the claim and it is unclear if “the prediction” is meant to refer back to “the prediction of radiotherapy response” as recited in claim 1, from which claim 8 depends from. In addition, the phrase "such as" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). In addition, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention.
Regarding claim 9, the claim recites the limitation “the prediction” in lines 2 & 3 of the claim and there is insufficient antecedent basis for this limitation in the claim and it is unclear if “the prediction” is meant to refer back to “the prediction of radiotherapy response” as recited in claim 1, from which claim 9 depends from.
Regarding claim 12, the claim recites the limitation “use of the kit” in line 1 of the claim and there is insufficient antecedent basis for this limitation in the claim. In addition, the phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). In addition, the recitation of “CDK12, FANCA, MRE11 and PALB2” in line 7 of the claim is unclear if MRE11 and PALB2 are part of the same group of genes or if this is the result of a typographical error and should read “CDK12, FANCA, MRE11, and PALB2”.
Regarding claim 14, the phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). In addition, the recitation of “CDK12, FANCA, MRE11 and PALB2” in lines 4-5 of the claim is unclear if MRE11 and PALB2 are part of the same group of genes or if this is the result of a typographical error and should read “CDK12, FANCA, MRE11, and PALB2”. In addition, the claim recites the limitation “the prediction” in line 7 of the claim and there is insufficient antecedent basis for this limitation in the claim. In addition, the recitation of “determining the prediction of the radiotherapy response based on the gene expression levels for three of more genes” in lines 7-8 of the claim is unclear what the relationship is between the prediction of radiotherapy response and the expression levels of three or more genes. Does increased or decreased expression indicate a particular prediction of radiotherapy response? How does the expression level of three or more target genes relate back to prediction of radiotherapy response and how does difference in expression levels of the three or more genes favor a particular prediction for radiotherapy response?
Claim 15 is rejected due to its dependence on claim 1 and claims 6 & 16 are rejected due to their dependence on claim 4.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 3-9, 12, & 14-16 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural correlation/law of nature and an abstract idea without significantly more. This judicial exception is not integrated into a practical application and the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons set forth below.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106. The unpatentability of abstract ideas was confirmed by the U.S. Supreme court in Bilski v. Kappos, 561 U.S. 593, 601 (June 28, 2010) and Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 134 S. Ct. 2347, 2354 (2014). See also Myriad v Ambry, CAFC 2014-1361, -1366, December 17, 2014. The unpatentability of laws of nature was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. 66, 71 (2012). “[L]aws of nature, natural phenomena, and abstract ideas” are not patentable. Dia-mond v. Diehr, 450 U. S. 175, 185 (1981); see also Bilski v. Kappos, 561 U. S. at 601 (2010).
Claims Analysis:
As set forth in MPEP 2106, the claims have been analyzed to determine whether they are directed to one of the four statutory categories (STEP 1).
The instant claims are directed to methods and therefore are directed to one of the four statutory categories of invention.
The claims are then analyzed to determine if they recite a judicial exception (JE) (STEP 2A, prong 1) [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)].
The claimed invention recites a method for predicting a response of a prostate cancer subject to radiotherapy comprising determining or receiving the result of a determination of the gene expression level of three or more genes and determining the prediction of the radiotherapy response based on the gene expression levels for three or more genes. This recitation is a natural correlation between expression levels of three or more genes and prediction of radiotherapy response. With regard to the natural correlation, as in Mayo, the relationship is itself a natural process that exists apart from any human action. The claimed invention also recites “determining or receiving the result of a determination of the gene expression levels of each of three or more genes” and “determining the prediction of the radiotherapy response” which is a recitation of an abstract idea because it encompasses reading a report and conclusions and determinations which can occur entirely within the mind. It is therefore determined that the claims are directed to judicial exceptions.
The claims are then analyzed to determine whether they recite an element or step that integrates the JE into a practical application (STEP 2A, prong 2) [Vanda Pharmaceuticals Inc., v. West-Ward Pharmaceuticals, 887 F.3d 1117 (Fed. Cir. 2018)].
The claims recite steps of determining or receiving the result of a determination of the gene expression levels of each of three or more genes, determining the prediction of the radiotherapy response based on the gene expression levels of the three or more genes and based on one or more clinical parameters, however this does not integrate the JE into a practical application because it is a mere data gathering step to use the correlation and does not add a meaningful limitation to the method.
Although the claims recite “if the prediction is non-favorable, the recommended therapy comprises one or more of (i) radiotherapy … (iv) an alternative therapy” or “if the prediction is favorable, the recommended therapy comprises one or more of: (vi) salvage therapy … (vii) watchful waiting”, this step is conditional as it is “based on” the expression levels of three or more genes determining a prediction for radiotherapy response. Accordingly, these generally recited elements are considered nothing more than instructions to apply the law of nature because no particular conditions are required by the step of detecting gene expression. As such, the “administering” step is merely a generalized “treat” limitation with no particularity that integrates the judicial exception into a practical application. The Supreme Court does acknowledge that it is possible to transform an unpatentable law of nature, but one must do more than simply state the law of nature while adding the words "apply it.” CLS BankInt’l, 134 S.Ct. at 2358; Prometheus, 132 S. Cl, at 1294.
In the absence of steps or elements that integrate the JE into a practical application, the additional elements/steps are considered to determine whether they add significantly more to the JE either individually or as an ordered combination, to “’transform the nature of the claim’ into a patent eligible application” [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)] (STEP 2B).
In the instant situation, the steps of determining or receiving the result of the determination of the gene expression levels of three or more genes are generally recited and do not provide any particular reagents that might be considered elements that transform the nature of the claims into a patent eligible application because no specific elements/steps are recited. This step is not only a mere data gathering step, but the general recitation of detection of known nucleic acids is well understood, routine, and conventional activity (See MPEP 2106.05(d)(II)). Applicant is reminded that in Mayo, the Court found that “[i]f a law of nature is not patentable, then neither is a process reciting a law of nature, unless that process has additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself." Further "conventional or obvious" "[pre]solution activity" is normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such a law”. Flook, 437 U. S., at 590; see also Bilski, 561 U. S., at ___ (slip op., at 14) (“[T]he prohibition against patenting abstract ideas ‘cannot be circumvented by’ . . . adding ‘insignificant post-solution activity’” (quoting Diehr, supra, at 191–192)). The Court also summarized their holding by stating “[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.” Therefore these limitations/steps do not “‘transform the nature of the claim’ into a patent-eligible application.’” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
When viewed as an ordered combination, the claimed limitations are directed to nothing more than the determination that a natural correlation/phenomena exists. Any additional element consists of using well understood, routine and conventional activity, and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.
Accordingly, it is determined that the instant claims are not directed to patent eligible subject matter.
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.
Claim(s) 1, 3-9, 12, & 14-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Vergis (Vergis et al.; Int. J. Radiation Oncology Biol. Phys., Vol. 78, pages 35-41, July 2009), as cited on the IDS dated 01/22/2024, in view of Smirnov (WO 2022/009051 A1, July 2nd, 2021) and Damaraju (Damaraju et al.; Cancer Therapy: Clinical, Vol. 12, pages 2545-2554, April 2006).
Regarding claim 1, Vergis teaches a method for determining markers of prostate cancer outcome and specifically markers for determining radiotherapy response to determine which could benefit from radiotherapy dose escalation (prediction is favorable or a non-favorable response to radiotherapy) comprising measuring the expression level of three of more genes and determining the choice of subsequent radiotherapy dose (salvage radiotherapy) in individual patients from the measured expression levels (determining or receiving the result of a determination of the gene expression levels of three or more genes and determining the prediction of the radiotherapy response based on the gene expression levels for the three or more genes) (abstract purpose lines 1-3; abstract methods and materials lines 1-4; abstract conclusions lines 1-4; pg. 35 paragraph bridging column 1 & 2 lines 1-16; pg. 36 column 1 1st full paragraph lines 1-7; pg. 36 paragraph bridging column 1 & 2 lines 1-15; pg. 36 column 2 1st full paragraph lines 1-13; pg. 38 column 2 1st full paragraph lines 1-11; pg. 40 column 2 2nd full paragraph lines 1-9).
Vergis does not teach the three or more genes are selected from HOXB13, KLK3, and MLH1.
Smirnov teaches a method for monitoring responsiveness of a subject having prostate cancer to a therapeutic agent comprising evaluating the expression or one or more prostate cancer biomarkers comprising HOXB13 and KLK3 wherein the therapeutic agent comprises radiation therapy (paragraph [0008] lines 1-14; paragraph [0413] lines 1-14; paragraph [0419] lines 1-3). Smirnov also teaches that some prostate cancer patients do not respond or become resistant to treatments providing a method for monitoring responsiveness of a therapeutic to tailor and determine effectiveness of treatment (paragraph [0004] lines 5-9; paragraph [0008] lines 1-14).
Damaraju teaches a method for identifying genes that are markers for predicting an individual with prostate cancer risk for complications arising from radiation therapy comprising measuring the expression level of MLH1 (abstract results lines 1-6; abstract conclusions lines 1-3; pg. 2546 column 1 2nd full paragraph lines 1-24; pg. 2546 paragraph bridging column 1 & 2 lines 1-19; pg. 2548-2549 paragraph bridging pg. 2548 & 2549 lines 1-9; pg. 2553 column 2 1st full paragraph lines 1-15; Table 2). Damaraju also teaches that this method identifies markers enabling prediction of adverse radiotherapy toxicity response and can aid in construction of predictive risk models for radiotherapy toxicity in patients with prostate cancer undergoing dose-escalated radiotherapy with curative intent (pg. 2553 column 2 1st full paragraph lines 1-15).
Vergis, Smirnov, and Damaraju are considered to be analogous to the claimed invention because they are all in the same field of determining expression values of genes for prediction of radiotherapeutic response in prostate cancer. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of determining markers of prostate cancer outcome and radiotherapy response to determine which could benefit from radiotherapy dose escalation comprising measuring the expression level of three of more genes and determining the choice of subsequent radiotherapy dose (salvage radiotherapy) in Vergis to incorporate evaluating the expression or one or more prostate cancer biomarkers comprising HOXB13 and KLK3 to monitor responsiveness to a therapeutic agent comprising radiotherapy as taught in Smirnov because Smirnov teaches that doing so would provide a method for monitoring responsiveness of a therapeutic to tailor and determine effectiveness of treatment and it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate measuring the expression level of MLH1 to predict radiation therapy complications in prostate cancer individuals as taught in Damaraju because Damaraju teaches that doing so would identifies markers for prediction of adverse radiotherapy toxicity response which can aid in construction of predictive risk models for radiotherapy toxicity in patients with prostate cancer undergoing dose-escalated radiotherapy with curative intent.
Regarding claim 3, Vergis teaches performing a Cox regression analysis with clinical factors and molecular marker expression levels from the patients with prostate cancer (combining the gene expression levels of three or more genes with a regression function that had been derived from a population of prostate cancer subjects) (pg. 36 column 1 2nd full paragraph lines 1-10; pg. 37 paragraph bridging column 1 & 2 lines 1-24).
Regarding claim 4, Vergis teaches the prediction of radiotherapy response and determining the choice of subsequent radiotherapy dose (salvage radiotherapy) comprises measuring serum PSA levels in the prostate cancer patients (prediction of the radiotherapy response is further based on one or more clinical parameters obtained from the subject) (pg. 37 paragraph bridging column 1 & 2 lines 1-24).
Regarding claim 5, Vergis teaches measuring serum PSA levels in the prostate cancer patients (one or more clinical parameters comprises PSA level) (pg. 36 paragraph bridging column 1 & 2 lines 14-15; pg. 37 paragraph bridging column 1 & 2 lines 1-24).
Regarding claim 6, Vergis teaches performing a Cox regression analysis with clinical factors and molecular marker expression levels from the patients with prostate cancer (combining the gene expression levels of three or more genes and the one or more clinical parameters obtained from the subject with a regression function that had been derived from a population of prostate cancer subjects) (pg. 36 column 1 2nd full paragraph lines 1-10; pg. 37 paragraph bridging column 1 & 2 lines 1-24).
Regarding claim 7, Vergis teaches the prostate cancer patient samples were from previously untreated prostate cancer samples (biological sample is obtained from the subject before the start of radiotherapy, preferably wherein the biological sample is a prostate sample or prostate cancer sample) (pg. 36 paragraph bridging column 1 & 2 lines 1-5).
Regarding claim 8, Vergis teaches the prediction of radiotherapy response and determining the choice of subsequent radiotherapy dose (salvage radiotherapy) comprises patients determined with poor outcome with dose-escalation radiotherapy (prediction is non-favorable) then the patient should be considered for long-term adjuvant androgen deprivation therapy or alternative gene targeted therapy (is prediction is non-favorable the recommended therapy comprises one or more of an adjuvant therapy, an alternative therapy that is not radiation therapy) (pg. 38-40 paragraph bridging pg. 38 & 40 lines 25-30).
Regarding claim 9, Vergis teaches the prediction of radiotherapy response and determining the choice of subsequent radiotherapy dose (salvage radiotherapy) comprises patients determined to benefit from dose-escalation radiotherapy (prediction is favorable) then the choice of radiotherapy dose can be made (if prediction is favorable the recommended therapy comprises one or more of salvage radiotherapy, watchful waiting) (pg. 40 column 1 1st full paragraph lines 1-11; pg. 40 column 1 2nd full paragraph lines 1-9).
Regarding claim 12, Vergis teaches determining markers of prostate cancer outcome and specifically markers for determining radiotherapy response to determine which could benefit from radiotherapy dose escalation comprising measuring the expression level of three of more genes and determining the choice of subsequent radiotherapy dose (salvage radiotherapy) in individual patients from the measured expression levels (use of kit in a method of predicting a response of a prostate cancer subject to radiotherapy) (abstract purpose lines 1-3; abstract methods and materials lines 1-4; abstract conclusions lines 1-4; pg. 35 paragraph bridging column 1 & 2 lines 1-16; pg. 36 column 1 1st full paragraph lines 1-7; pg. 36 paragraph bridging column 1 & 2 lines 1-15; pg. 36 column 2 1st full paragraph lines 1-13; pg. 38 column 2 1st full paragraph lines 1-11; pg. 40 column 2 2nd full paragraph lines 1-9).
Vergis does not teach the three or more genes are selected from HOXB13, KLK3, and MLH1 and at least three sets of polymerase chain rection primer pairs for the determining the expression of HOXB13, KLK3, and MLH1.
Smirnov teaches a method for monitoring responsiveness of a subject having prostate cancer to a therapeutic agent comprising evaluating the expression or one or more prostate cancer biomarkers comprising HOXB13 and KLK3 comprising measuring the expression of the prostate cancer biomarkers HOXB13 and KLK3 through PCR (use of kit of polymerase chain reaction primer pairs for HOXB13 and KLK3) (paragraph [0008] lines 1-14; paragraph [0413] lines 1-14; paragraph [0419] lines 1-3). Smirnov also teaches that some prostate cancer patients do not respond or become resistant to treatments providing a method for monitoring responsiveness of a therapeutic to tailor and determine effectiveness of treatment (paragraph [0004] lines 5-9; paragraph [0008] lines 1-14).
Damaraju teaches a method for identifying genes that are markers for predicting an individual with prostate cancer risk for complications arising from radiation therapy comprising measuring the expression level of MLH1 with oligonucleotide primers for PCR (use of kit of polymerase chain reaction primer pair for MLH1) (abstract results lines 1-6; abstract conclusions lines 1-3; pg. 2546 column 1 2nd full paragraph lines 1-24; pg. 2546 paragraph bridging column 1 & 2 lines 1-19; pg. 2548-2549 paragraph bridging pg. 2548 & 2549 lines 1-9; pg. 2553 column 2 1st full paragraph lines 1-15; Table 2). Damaraju also teaches that this method identifies markers enabling prediction of adverse radiotherapy toxicity response and can aid in construction of predictive risk models for radiotherapy toxicity in patients with prostate cancer undergoing dose-escalated radiotherapy with curative intent (pg. 2553 column 2 1st full paragraph lines 1-15).
Vergis, Smirnov, and Damaraju are considered to be analogous to the claimed invention because they are all in the same field of determining expression values of genes for prediction of radiotherapeutic response in prostate cancer. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the use of a kit for predicting radiotherapy response to determine which could benefit from radiotherapy dose escalation comprising measuring the expression level of three of more genes in Vergis to incorporate measuring the expression of the prostate cancer biomarkers HOXB13 and KLK3 through PCR (use of kit of polymerase chain reaction primer pairs for HOXB13 and KLK3) as taught in Smirnov because Smirnov teaches that doing so would provide a method for monitoring responsiveness of a therapeutic to tailor and determine effectiveness of treatment and it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate measuring the expression level of MLH1 with oligonucleotide primers for PCR (use of kit of polymerase chain reaction primer pair for MLH1) as taught in Damaraju because Damaraju teaches that doing so would identifies markers for prediction of adverse radiotherapy toxicity response which can aid in construction of predictive risk models for radiotherapy toxicity in patients with prostate cancer undergoing dose-escalated radiotherapy with curative intent.
Regarding claim 14, Vergis teaches a method for determining markers of prostate cancer outcome and specifically markers for determining radiotherapy response to determine which could benefit from radiotherapy dose escalation (prediction is favorable or a non-favorable response to radiotherapy) comprising measuring the expression level of three of more genes and determining the choice of subsequent radiotherapy dose (salvage radiotherapy) in individual patients from the measured expression levels (use of gene expression profile of three or more genes and determining the prediction of the radiotherapy response based on the gene expression levels for the three or more genes) (abstract purpose lines 1-3; abstract methods and materials lines 1-4; abstract conclusions lines 1-4; pg. 35 paragraph bridging column 1 & 2 lines 1-16; pg. 36 column 1 1st full paragraph lines 1-7; pg. 36 paragraph bridging column 1 & 2 lines 1-15; pg. 36 column 2 1st full paragraph lines 1-13; pg. 38 column 2 1st full paragraph lines 1-11; pg. 40 column 2 2nd full paragraph lines 1-9).
Vergis does not teach the three or more genes are selected from HOXB13, KLK3, and MLH1.
Smirnov teaches a method for monitoring responsiveness of a subject having prostate cancer to a therapeutic agent comprising evaluating the expression or one or more prostate cancer biomarkers comprising HOXB13 and KLK3 wherein the therapeutic agent comprises radiation therapy (paragraph [0008] lines 1-14; paragraph [0413] lines 1-14; paragraph [0419] lines 1-3). Smirnov also teaches that some prostate cancer patients do not respond or become resistant to treatments providing a method for monitoring responsiveness of a therapeutic to tailor and determine effectiveness of treatment (paragraph [0004] lines 5-9; paragraph [0008] lines 1-14).
Damaraju teaches a method for identifying genes that are markers for predicting an individual with prostate cancer risk for complications arising from radiation therapy comprising measuring the expression level of MLH1 (abstract results lines 1-6; abstract conclusions lines 1-3; pg. 2546 column 1 2nd full paragraph lines 1-24; pg. 2546 paragraph bridging column 1 & 2 lines 1-19; pg. 2548-2549 paragraph bridging pg. 2548 & 2549 lines 1-9; pg. 2553 column 2 1st full paragraph lines 1-15; Table 2). Damaraju also teaches that this method identifies markers enabling prediction of adverse radiotherapy toxicity response and can aid in construction of predictive risk models for radiotherapy toxicity in patients with prostate cancer undergoing dose-escalated radiotherapy with curative intent (pg. 2553 column 2 1st full paragraph lines 1-15).
Vergis, Smirnov, and Damaraju are considered to be analogous to the claimed invention because they are all in the same field of determining expression values of genes for prediction of radiotherapeutic response in prostate cancer. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of determining markers of prostate cancer outcome and radiotherapy response to determine which could benefit from radiotherapy dose escalation comprising measuring the expression level of three of more genes and determining the choice of subsequent radiotherapy dose (salvage radiotherapy) in Vergis to incorporate evaluating the expression or one or more prostate cancer biomarkers comprising HOXB13 and KLK3 to monitor responsiveness to a therapeutic agent comprising radiotherapy as taught in Smirnov because Smirnov teaches that doing so would provide a method for monitoring responsiveness of a therapeutic to tailor and determine effectiveness of treatment and it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate measuring the expression level of MLH1 to predict radiation therapy complications in prostate cancer individuals as taught in Damaraju because Damaraju teaches that doing so would identifies markers for prediction of adverse radiotherapy toxicity response which can aid in construction of predictive risk models for radiotherapy toxicity in patients with prostate cancer undergoing dose-escalated radiotherapy with curative intent.
Regarding claim 15, Smirnov teaches evaluating the expression or one or more prostate cancer biomarkers comprising HOXB13 and KLK3 (paragraph [0008] lines 1-14; paragraph [0413] lines 1-14; paragraph [0419] lines 1-3).
Damaraju teaches a method for identifying genes that are markers for predicting an individual with prostate cancer risk for complications arising from radiation therapy comprising measuring the expression level of MLH1 (abstract results lines 1-6; abstract conclusions lines 1-3; pg. 2546 column 1 2nd full paragraph lines 1-24; pg. 2546 paragraph bridging column 1 & 2 lines 1-19; pg. 2548-2549 paragraph bridging pg. 2548 & 2549 lines 1-9; pg. 2553 column 2 1st full paragraph lines 1-15; Table 2).
Regarding claim 16, Vergis teaches measuring serum PSA levels in the prostate cancer patients (one or more clinical parameters comprises PSA level) (pg. 36 paragraph bridging column 1 & 2 lines 14-15; pg. 37 paragraph bridging column 1 & 2 lines 1-24).
Claim(s) 1, 3-9, 12, & 14-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Vergis (Vergis et al.; Int. J. Radiation Oncology Biol. Phys., Vol. 78, pages 35-41, July 2009), as cited on the IDS dated 01/22/2024, in view of Stone (United State Patent Application Publication US 2017/0152571 A1), as cited on the IDS dated 01/22/2024, and Damaraju (Damaraju et al.; Cancer Therapy: Clinical, Vol. 12, pages 2545-2554, April 2006).
Regarding claim 1, Vergis teaches a method for determining markers of prostate cancer outcome and specifically markers for determining radiotherapy response to determine which could benefit from radiotherapy dose escalation (prediction is favorable or a non-favorable response to radiotherapy) comprising measuring the expression level of three of more genes and determining the choice of subsequent radiotherapy dose (salvage radiotherapy) in individual patients from the measured expression levels (determining or receiving the result of a determination of the gene expression levels of three or more genes and determining the prediction of the radiotherapy response based on the gene expression levels for the three or more genes) (abstract purpose lines 1-3; abstract methods and materials lines 1-4; abstract conclusions lines 1-4; pg. 35 paragraph bridging column 1 & 2 lines 1-16; pg. 36 column 1 1st full paragraph lines 1-7; pg. 36 paragraph bridging column 1 & 2 lines 1-15; pg. 36 column 2 1st full paragraph lines 1-13; pg. 38 column 2 1st full paragraph lines 1-11; pg. 40 column 2 2nd full paragraph lines 1-9).
Vergis does not teach the three or more genes are selected from HOXB13, KLK3, and MLH1.
Stone teaches a method of determining from patient diagnosed with prostate cancer the expression level of a panel of genes (three or more genes) to predict prognosis and further recommend, prescribe, or administer a treatment comprising radiation therapy comprising measuring the expression levels of KLK3 and HOXB13 (paragraph [0013] lines 1-19; paragraph [0077] lines 1-8; paragraph [0445] lines 1-19; paragraph [0446] lines 1-7; paragraph [0453] lines 1-7; paragraph [0467] lines 1-9; Table Y). Stone also teaches that this method is particularly useful in prognosis and predicting treatment in prostate cancer (paragraph [0006] lines 1-6; paragraph [0013] lines 1-19).
Damaraju teaches a method for identifying genes that are markers for predicting an individual with prostate cancer risk for complications arising from radiation therapy comprising measuring the expression level of MLH1 (abstract results lines 1-6; abstract conclusions lines 1-3; pg. 2546 column 1 2nd full paragraph lines 1-24; pg. 2546 paragraph bridging column 1 & 2 lines 1-19; pg. 2548-2549 paragraph bridging pg. 2548 & 2549 lines 1-9; pg. 2553 column 2 1st full paragraph lines 1-15; Table 2). Damaraju also teaches that this method identifies markers enabling prediction of adverse radiotherapy toxicity response and can aid in construction of predictive risk models for radiotherapy toxicity in patients with prostate cancer undergoing dose-escalated radiotherapy with curative intent (pg. 2553 column 2 1st full paragraph lines 1-15).
Vergis, Stone, and Damaraju are considered to be analogous to the claimed invention because they are all in the same field of determining expression values of genes for prediction of radiotherapeutic response in prostate cancer. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of determining markers of prostate cancer outcome and radiotherapy response to determine which could benefit from radiotherapy dose escalation comprising measuring the expression level of three of more genes and determining the choice of subsequent radiotherapy dose (salvage radiotherapy) in Vergis to incorporate determining the expression prostate cancer biomarkers comprising HOXB13 and KLK3 to predict prognosis and further recommend treatment as taught in Stone because Stone teaches that doing so would provide a method that is particularly useful in prognosis and predicting treatment in prostate cancer and it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate measuring the expression level of MLH1 to predict radiation therapy complications in prostate cancer individuals as taught in Damaraju because Damaraju teaches that doing so would identifies markers for prediction of adverse radiotherapy toxicity response which can aid in construction of predictive risk models for radiotherapy toxicity in patients with prostate cancer undergoing dose-escalated radiotherapy with curative intent.
Regarding claim 3, Vergis teaches performing a Cox regression analysis with clinical factors and molecular marker expression levels from the patients with prostate cancer (combining the gene expression levels of three or more genes with a regression function that had been derived from a population of prostate cancer subjects) (pg. 36 column 1 2nd full paragraph lines 1-10; pg. 37 paragraph bridging column 1 & 2 lines 1-24).
Regarding claim 4, Vergis teaches the prediction of radiotherapy response and determining the choice of subsequent radiotherapy dose (salvage radiotherapy) comprises measuring serum PSA levels in the prostate cancer patients (prediction of the radiotherapy response is further based on one or more clinical parameters obtained from the subject) (pg. 37 paragraph bridging column 1 & 2 lines 1-24).
Regarding claim 5, Vergis teaches measuring serum PSA levels in the prostate cancer patients (one or more clinical parameters comprises PSA level) (pg. 36 paragraph bridging column 1 & 2 lines 14-15; pg. 37 paragraph bridging column 1 & 2 lines 1-24).
Regarding claim 6, Vergis teaches performing a Cox regression analysis with clinical factors and molecular marker expression levels from the patients with prostate cancer (combining the gene expression levels of three or more genes and the one or more clinical parameters obtained from the subject with a regression function that had been derived from a population of prostate cancer subjects) (pg. 36 column 1 2nd full paragraph lines 1-10; pg. 37 paragraph bridging column 1 & 2 lines 1-24).
Regarding claim 7, Vergis teaches the prostate cancer patient samples were from previously untreated prostate cancer samples (biological sample is obtained from the subject before the start of radiotherapy, preferably wherein the biological sample is a prostate sample or prostate cancer sample) (pg. 36 paragraph bridging column 1 & 2 lines 1-5).
Regarding claim 8, Vergis teaches the prediction of radiotherapy response and determining the choice of subsequent radiotherapy dose (salvage radiotherapy) comprises patients determined with poor outcome with dose-escalation radiotherapy (prediction is non-favorable) then the patient should be considered for long-term adjuvant androgen deprivation therapy or alternative gene targeted therapy (is prediction is non-favorable the recommended therapy comprises one or more of an adjuvant therapy, an alternative therapy that is not radiation therapy) (pg. 38-40 paragraph bridging pg. 38 & 40 lines 25-30).
Regarding claim 9, Vergis teaches the prediction of radiotherapy response and determining the choice of subsequent radiotherapy dose (salvage radiotherapy) comprises patients determined to benefit from dose-escalation radiotherapy (prediction is favorable) then the choice of radiotherapy dose can be made (if prediction is favorable the recommended therapy comprises one or more of salvage radiotherapy, watchful waiting) (pg. 40 column 1 1st full paragraph lines 1-11; pg. 40 column 1 2nd full paragraph lines 1-9).
Regarding claim 12, Vergis teaches determining markers of prostate cancer outcome and specifically markers for determining radiotherapy response to determine which could benefit from radiotherapy dose escalation comprising measuring the expression level of three of more genes and determining the choice of subsequent radiotherapy dose (salvage radiotherapy) in individual patients from the measured expression levels (use of kit in a method of predicting a response of a prostate cancer subject to radiotherapy) (abstract purpose lines 1-3; abstract methods and materials lines 1-4; abstract conclusions lines 1-4; pg. 35 paragraph bridging column 1 & 2 lines 1-16; pg. 36 column 1 1st full paragraph lines 1-7; pg. 36 paragraph bridging column 1 & 2 lines 1-15; pg. 36 column 2 1st full paragraph lines 1-13; pg. 38 column 2 1st full paragraph lines 1-11; pg. 40 column 2 2nd full paragraph lines 1-9).
Vergis does not teach the three or more genes are selected from HOXB13, KLK3, and MLH1 and at least three sets of polymerase chain rection primer pairs for the determining the expression of HOXB13, KLK3, and MLH1.
Stone teaches a method of determining from patient diagnosed with prostate cancer the expression level of a panel of genes (three or more genes) to predict prognosis and further recommend, prescribe, or administer a treatment comprising radiation therapy comprising measuring the expression levels of KLK3 and HOXB13 PCR oligonucleotides (use of a kit of polymerase chain reaction primer pairs for KLK3 and HOXB13) (paragraph [0013] lines 1-19; paragraph [0077] lines 1-8; paragraph [0445] lines 1-19; paragraph [0446] lines 1-7; paragraph [0453] lines 1-7; paragraph [0467] lines 1-9; Table Y). Stone also teaches that this method is particularly useful in prognosis and predicting treatment in prostate cancer (paragraph [0006] lines 1-6; paragraph [0013] lines 1-19).
Damaraju teaches a method for identifying genes that are markers for predicting an individual with prostate cancer risk for complications arising from radiation therapy comprising measuring the expression level of MLH1 with oligonucleotide primers for PCR (use of kit of polymerase chain reaction primer pair for MLH1) (abstract results lines 1-6; abstract conclusions lines 1-3; pg. 2546 column 1 2nd full paragraph lines 1-24; pg. 2546 paragraph bridging column 1 & 2 lines 1-19; pg. 2548-2549 paragraph bridging pg. 2548 & 2549 lines 1-9; pg. 2553 column 2 1st full paragraph lines 1-15; Table 2). Damaraju also teaches that this method identifies markers enabling prediction of adverse radiotherapy toxicity response and can aid in construction of predictive risk models for radiotherapy toxicity in patients with prostate cancer undergoing dose-escalated radiotherapy with curative intent (pg. 2553 column 2 1st full paragraph lines 1-15).
Vergis, Stone, and Damaraju are considered to be analogous to the claimed invention because they are all in the same field of determining expression values of genes for prediction of radiotherapeutic response in prostate cancer. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the use of a kit for predicting radiotherapy response to determine which could benefit from radiotherapy dose escalation comprising measuring the expression level of three of more genes in Vergis to incorporate measuring the expression of the prostate cancer biomarkers KLK3 and HOXB13 through PCR (use of kit of polymerase chain reaction primer pairs for HOXB13 and KLK3) as taught in Stone because Stone teaches that doing so would provide a method particularly useful in prognosis and predicting treatment in prostate cancer and it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate measuring the expression level of MLH1 with oligonucleotide primers for PCR (use of kit of polymerase chain reaction primer pair for MLH1) as taught in Damaraju because Damaraju teaches that doing so would identifies markers for prediction of adverse radiotherapy toxicity response which can aid in construction of predictive risk models for radiotherapy toxicity in patients with prostate cancer undergoing dose-escalated radiotherapy with curative intent.
Regarding claim 14, Vergis teaches a method for determining markers of prostate cancer outcome and specifically markers for determining radiotherapy response to determine which could benefit from radiotherapy dose escalation (prediction is favorable or a non-favorable response to radiotherapy) comprising measuring the expression level of three of more genes and determining the choice of subsequent radiotherapy dose (salvage radiotherapy) in individual patients from the measured expression levels (use of gene expression profile of three or more genes and determining the prediction of the radiotherapy response based on the gene expression levels for the three or more genes) (abstract purpose lines 1-3; abstract methods and materials lines 1-4; abstract conclusions lines 1-4; pg. 35 paragraph bridging column 1 & 2 lines 1-16; pg. 36 column 1 1st full paragraph lines 1-7; pg. 36 paragraph bridging column 1 & 2 lines 1-15; pg. 36 column 2 1st full paragraph lines 1-13; pg. 38 column 2 1st full paragraph lines 1-11; pg. 40 column 2 2nd full paragraph lines 1-9).
Vergis does not teach the three or more genes are selected from HOXB13, KLK3, and MLH1.
Stone teaches a method of determining from patient diagnosed with prostate cancer the expression level of a panel of genes (three or more genes) to predict prognosis and further recommend, prescribe, or administer a treatment comprising radiation therapy comprising measuring the expression levels of KLK3 and HOXB13 (paragraph [0013] lines 1-19; paragraph [0077] lines 1-8; paragraph [0445] lines 1-19; paragraph [0446] lines 1-7; paragraph [0453] lines 1-7; paragraph [0467] lines 1-9; Table Y). Stone also teaches that this method is particularly useful in prognosis and predicting treatment in prostate cancer (paragraph [0006] lines 1-6; paragraph [0013] lines 1-19).
Damaraju teaches a method for identifying genes that are markers for predicting an individual with prostate cancer risk for complications arising from radiation therapy comprising measuring the expression level of MLH1 (abstract results lines 1-6; abstract conclusions lines 1-3; pg. 2546 column 1 2nd full paragraph lines 1-24; pg. 2546 paragraph bridging column 1 & 2 lines 1-19; pg. 2548-2549 paragraph bridging pg. 2548 & 2549 lines 1-9; pg. 2553 column 2 1st full paragraph lines 1-15; Table 2). Damaraju also teaches that this method identifies markers enabling prediction of adverse radiotherapy toxicity response and can aid in construction of predictive risk models for radiotherapy toxicity in patients with prostate cancer undergoing dose-escalated radiotherapy with curative intent (pg. 2553 column 2 1st full paragraph lines 1-15).
Vergis, Stone, and Damaraju are considered to be analogous to the claimed invention because they are all in the same field of determining expression values of genes for prediction of radiotherapeutic response in prostate cancer. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of determining markers of prostate cancer outcome and radiotherapy response to determine which could benefit from radiotherapy dose escalation comprising measuring the expression level of three of more genes and determining the choice of subsequent radiotherapy dose (salvage radiotherapy) in Vergis to incorporate determining the expression prostate cancer biomarkers comprising HOXB13 and KLK3 to predict prognosis and further recommend treatment as taught in Stone because Stone teaches that doing so would provide a method that is particularly useful in prognosis and predicting treatment in prostate cancer and it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate measuring the expression level of MLH1 to predict radiation therapy complications in prostate cancer individuals as taught in Damaraju because Damaraju teaches that doing so would identifies markers for prediction of adverse radiotherapy toxicity response which can aid in construction of predictive risk models for radiotherapy toxicity in patients with prostate cancer undergoing dose-escalated radiotherapy with curative intent.
Regarding claim 15, Stone teaches a method of determining from patient diagnosed with prostate cancer the expression level of a panel of genes (three or more genes) to predict prognosis and further recommend, prescribe, or administer a treatment comprising radiation therapy comprising measuring the expression levels of KLK3 and HOXB13 (paragraph [0013] lines 1-19; paragraph [0077] lines 1-8; paragraph [0445] lines 1-19; paragraph [0446] lines 1-7; paragraph [0453] lines 1-7; paragraph [0467] lines 1-9; Table Y).
Damaraju teaches a method for identifying genes that are markers for predicting an individual with prostate cancer risk for complications arising from radiation therapy comprising measuring the expression level of MLH1 (abstract results lines 1-6; abstract conclusions lines 1-3; pg. 2546 column 1 2nd full paragraph lines 1-24; pg. 2546 paragraph bridging column 1 & 2 lines 1-19; pg. 2548-2549 paragraph bridging pg. 2548 & 2549 lines 1-9; pg. 2553 column 2 1st full paragraph lines 1-15; Table 2).
Regarding claim 16, Vergis teaches measuring serum PSA levels in the prostate cancer patients (one or more clinical parameters comprises PSA level) (pg. 36 paragraph bridging column 1 & 2 lines 14-15; pg. 37 paragraph bridging column 1 & 2 lines 1-24).
Conclusion
Claims 1, 3-9, 12, & 14-16 are rejected.
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/BAILEY BUCHANAN/Examiner, Art Unit 1682
/JEHANNE S SITTON/Primary Examiner, Art Unit 1682
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