DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 29 September 2025 has been entered. Claims 1-4, 9-10, 14-15, and 19 have been amended, and claim 17 has been canceled. All prior rejections of claim 17 are moot in view of the cancelation of that claim. Claims 1-16 and 18-22 remain under consideration herein.
Applicant’s amendments and arguments have been thoroughly reviewed, and have overcome the following objections/rejections set forth in the prior Office action:
The objection to the specification (related to new matter added by the amendment filed February 28, 2025), in view of Applicant’s amendments to paragraphs 153, 205, and 250;
The objections to the claims, in view of Applicant’s corrective amendments to claims 1, 10, and 15;
The rejections under 35 USC 112(b), in view of Applicant’s clarifying amendments;
The rejection of claims under 35 USC 102 as being anticipated by Papachristos et al, in view of the amendment of each of the independent claims to require an “administering” that follows the other recited method steps;
The rejection of claims under 35 USC 102 as being anticipated by Formica et al, again in view of the amendment of the independent claims to require an “administering” that follows the other recited method steps;
The rejection of claims under 35 USC 103 over Papachristos et al in view of Formica et al on the grounds indicated in the prior Office action (although it is noted that some amended claims remain rejected over this combination of references on the grounds indicated below); and
The rejections of claims 1 and 2 and claims dependent therefrom under 35 U.S.C. 101, in view of the amendment of each of the independent claims to required methods in which an active “treating” step is required to be performed as the final step in the series of ordered steps a)-c), such that the amended claims require a practical application of a JE.
Claims 1-9, 12-16, 18-19, and 21 remain/are rejected for the reasons given below, while claims 10-11, 20, and 22 are objected to (but no longer rejected). Any rejections and/or objections not reiterated in this action have been withdrawn. This action is non-final.
Foreign Priority/Correction of Filing Receipt is Required
The corrected Application Data Sheet filed 29 September 2025, deleting a foreign priority claim to UK application 1910731.7, is noted; however, in order to complete correction of the foreign priority claim (and to ensure consistency throughout Office records), Applicant must also request a corrected filing receipt (see MPEP 601.05(a)(II)).
Claim Interpretation
With regard to amended independent claim 4, it is noted that the claim is now directed to a “method of treating a subject” comprising “(a) identifying…the presence of” one or both of two recited particular polymorphisms in a sample from the subject and “(b) administering to the subject a combination therapy…..based on the identification of (a)”. Given the requirement in the “administering” of “the identification of (a)”, the claim is interpreted as requiring that (b) follow (a).
Claim Objections
Claims 1, 5-16, and 21-22 are objected to because of the following informalities in independent claim 1: the claim recites a “method of treating subject…” rather than a “method of treating a subject”. Appropriate correction is required. With further regard to claim 1, it is suggested that Applicant may wish to consider amending the claim at the second line of (b) to recite “and/or” rather than “or”, as the prior “identifying” employs “and/or”.
Claim 20 is objected to because of the following informalities: the claim fails to end in a period. Appropriate correction is required.
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) 1-4, 6-8, 12-16, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Papachristos et al (Journal of Clinical Oncology 36(15 Suppl):2521 [20 May 2018]; cited in IDS).
Regarding independent claim 1 and claims dependent therefrom, claim 1 as amended is drawn to a method “of treating subject having metastatic colorectal cancer (mCRC) comprising: (a) identifying, in a sample obtained from the subject, the presence of the ICAM-1 rs1799969 G/A allele polymorphism and/or VEGF-A rs699947 A/A allele polymorphism, or identifying the subject as having been identified as having the presence of” one or both of these polymorphisms; “(b) determining, based on identifying the presence of at least one of” the polymorphisms or “identifying the subject as having been identified as having the presence of’ one or both polymorphisms “that the subject is more likely to respond to treatment with” and/or “likely to have a longer overall survival when treated” with bevacizumab and fluoropyrimidine-based chemotherapy or a bevacizumab biosimilar and fluoropyrimidine-based chemotherapy therapy, and “c) following the determining, administering bevacizumab and fluoropyrimidine-based chemotherapy or a bevacizumab biosimilar and fluoropyrimidine-based chemotherapy based on determining that the subject is more likely” to respond or likely to have a longer overall survival.
Papachristos et al disclose “identifying the presence” of each of rs1799969 G/A and rs699947 A/A in subjects with metastatic colorectal cancer, which subjects were treated “with Bevacizumab and chemotherapy (fluoropyrimidines/ oxaliplatin or irinotecan)” (see entire Abstract); Papachristos et al thus teach both a type of identifying/genotyping meeting the requirements of a) and b) of claim 1, and an “administering” meeting the requirements of c) of claim 1, with the exception of the new limitation “following the determining, administering…”. Papachristos et al further disclose an association between rs699947 A/A and longer progression free survival, and teach that rs699947 is considered a “candidate response biomarker” that “might be able to stratify patients, who may gain a long-term benefit towards the optimization of Bevacizumab therapy and achieving better-informed therapeutic outcomes” (see “Conclusions”). While it is noted that Papachristos et al do not provide an analogous teaching for rs1799969 G/A, claim 1 recites identifying rs1799969 G/A and/or rs699947 A/A, and thus embraces methods involving the latter polymorphism alone.
In view of Papachristos et al’s own teachings, 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 Papachristos et al so as to have performed “administering” of the therapy taught by Papachristos et al with regard to subjects previously identified as having the rs699947 A/A allele polymorphism – either subjects not previously treated with bevacizumab and chemotherapy, or subjects already undergoing such treatment - and thereby to have performed a method meeting the requirements of the claims. An ordinary artisan would have been motivated to have made such a modification by Papachristos et al’s teachings that the purpose of their study identification of predictive biomarkers for response to such therapy, and their reported finding that rs699947 A/A is a possible such biomarker. While it is noted that Papachristos et al do not report, e.g., validation of their findings, given the characteristics of the patients being treated (include the reported PFS and OS), and the fact that the therapy in question is already in use in such patients (with rs699947 A/A carriers reported as showing significantly longer PFS), an ordinary artisan would have recognized such a modification as obvious over the teachings of Papachristos et al, and also would have had a reasonable expectation of success in performing such methods.
With further regard to the recitation in c) of claim 1 of the language “administering… based on determining that the subject is more likely to respond to treatment and/or likely to have a longer overall survival”, it is noted that this language does not impart any kind of manipulative difference to what is claimed beyond the requirement for an “administering” performed “following the determining”, but rather simply adds an instructional limitation to the method suggested by the prior art; such a limitation is nonfunctional descriptive material that is not given patentable weight when comparing the claimed invention to the prior art (and furthermore, Papachristos et al suggests the increased likelihood of survival associated with rs699947 A/A, as discussed above).
With further regard to dependent claim 6, Papachristos et al teach the alternative of PCR-based Sanger sequencing, such that PCR is disclosed (see the Abstract under “Methods”). Regarding claims 7-8, as these claims encompass further limitation of what is indicated as a result of the method step of “determining, based on identifying…”, the claims are obvious at least to the extent that they are directed to the embodiment of what is determined with regard to likelihood of response and/or overall survival (as this does not result in any manipulative difference in what is claimed). (With regard to such “wherein” clauses, it is noted that claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed; see MPEP 2111.04). Regarding claims 12-14, these claims similarly recite “wherein” clauses that correspond to properties indicated by the result of the “identifying” and “determining” of claim 1, rather than setting forth any type of required further action/manipulation (or any required further limitation of a structure, etc., as would be necessary for the “wherein” clause to limit what is claimed [see MPEP 2111.04]). Claims 15-16 recite “wherein” clauses setting forth properties that a subject “will have” as a result of an outcome of the “identifying” of claim 1 “when treated with bevacizumab and fluoropyrimidine-based chemotherapy”, etc.; however, the claims as written do not require such subjects (and thus these claims are obvious for the reasons given above).
Regarding independent claim 2 and claims dependent therefrom, claim 2 as amended is drawn to a method “of selecting a treatment for a subject’s metastatic colorectal cancer, the method comprising: (a) identifying, in a sample obtained from the subject, the absence of the ICAM-1 rs1799969 G/A allele polymorphism and the VEGF-A rs699947 A/A allele polymorphism; (b) following the identifying, selecting a treatment comprising a fluoropyrimidine-based chemotherapy; and (c) administering the selected treatment comprising the fluoropyrimidine based chemotherapy”. It is noted that the claim as amended embrace any type of therapy including a fluoropyrimidine-based therapy (including the combination therapies taught by Papachristos et al, as the claim no longer species such a treatment “only”). While Papachristos et al do not teach a particular benefit of employing bevacizumab in subject’s lacking rs699947 A/A, they do teach the use of a therapy meeting the requirements of the claims in all types of subjects regardless of rs1799969 and rs699947 genotype, and do not teach, e.g., the need to discontinue therapy for any reason (including based on any pattern associated with genotype). Thus, given the breadth of the claims and the fact that they encompass any type of therapy including any “fluoropyrimidine-based chemotherapy”, an ordinary artisan would have been motivated to have performed such an administering regardless of detected genotype, simply for the benefit of treating an mCRC patient with a known therapy therefore (although it is noted that this rejection could be overcome by amending the claim to again require “fluoropyrimidine-based chemotherapy alone”).
Regarding dependent claim 19, it is reiterated that Papachristos et al teach the alternative of PCR-based Sanger sequencing, such that PCR is disclosed.
Regarding independent claims 3-4, these claims as amended – like claim 1 – are directed to methods of treating a subject having mCRC comprising identifying in a sample obtained from the subject rs1799969 G/A and/or rs699947 A/A; claim 3 further requires administering a therapy of the type specified in claim 1 “following the identifying”, while claim 4 further requires such an administering “based on the identification of a)” (such that the administering follows the identifying). These claims thus require a combination of steps as discussed above with regard to claim 1, and are obvious for the same reasons given above with regard to that claim. It is also particularly noted that Papachristos et al disclose treating subjects with a combination of bevacizumab and “chemotherapy (fluoropyrimidines/oxaliplatin or irinotecan)”, and thus disclose a drug “combination therapy”; and again, the claims only require one of rs1799969 and rs699947.
Claim(s) 1, 3-9, 12-14, 16, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Formica et al (Int. J. Colorectal Dis. 26:143-151 [2011; online Dec 2010]; cited in IDS).
It is noted that this rejection applies to the claims as directed to the alternative of rs699947 A/A (i.e., while Formica et al do not teach rs1799969, the rejected claims recite rs699947 “and/or” rs1799969, such that either SNP alone is embraced by the rejected claims).
Regarding independent claim 1 and claims dependent therefrom, Formica et al teach methods in which genotyping of several VEGF polymorphisms - including rs699947 - is performed on subjects treated for mCRC with a combination of bevacizumab and a fluoropyrimidine (specifically fluorouracil, in the combination FOLFIRI); see entire reference, particularly the Abstract, and pages 144-145, including Table 1 (particularly the first entry). It is noted that Formica et al teach analysis of a group of SNPs in complete linkage disequilibrium and thus analysis as a haplotype; rs699947 corresponds to position -2578, listed as the first allele of the haplotype, with Haplo1 including the A allele of rs699947, and Haplo2 the C allele (see the Abstract “Results” at page 143, right column, page 145, particularly the first entry of Table 1, and page 146, particularly the 7th full paragraph in the left column, and the 6th full paragraph of the right column). Formica et al also report that subjects homozygous Haplo2 (including rs699947 allele C) “had significantly shorter” median progression free survival (mPFS) as compared to other patients (corresponding to heterozygous rs699947 A/C and homozygous rs699947 A/A patients); see page 146, right column, 6th full paragraph).
As previously noted, claim 1 as amended is drawn to a method “of treating subject having metastatic colorectal cancer (mCRC) comprising: (a) identifying, in a sample obtained from the subject, the presence of the ICAM-1 rs1799969 G/A allele polymorphism and/or VEGF-A rs699947 A/A allele polymorphism, or identifying the subject as having been identified as having the presence of” one or both of these polymorphisms; “(b) determining, based on identifying the presence of at least one of” the polymorphisms or “identifying the subject as having been identified as having the presence of’ one or both polymorphisms “that the subject is more likely to respond to treatment with” and/or “likely to have a longer overall survival when treated” with bevacizumab and fluoropyrimidine-based chemotherapy or a bevacizumab biosimilar and fluoropyrimidine-based chemotherapy therapy, and “c) following the determining, administering bevacizumab and fluoropyrimidine-based chemotherapy or a bevacizumab biosimilar and fluoropyrimidine-based chemotherapy based on determining that the subject is more likely” to respond or likely to have a longer overall survival. The claims thus require performing the recited “administering” following the “identifying” and “determining”, such that the order of steps taught by Formica et al differs from those of the claims. However, in view of Formica et al’s own teachings,
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 Formica et al so as to have performed “administering” of the therapy taught by Formica et al with regard to subjects previously identified as having the rs699947 A/A allele polymorphism (or the rs699947 A/C allele) – either subjects not previously treated with bevacizumab and FOLFIRI, or subjects already undergoing such treatment - and thereby to have performed a method meeting the requirements of the claims. An ordinary artisan would have been motivated to have made such a modification by Formica et al’s teachings that such subjects were found to exhibit longer mPFS as compared to rs699947 C/C subjects. While it is noted that Formica et al teach that further study is required (page 150), based on the evidence of benefit already provided by Formica et al, an ordinary artisan would have recognized such a modification as obvious, and also would have had a reasonable expectation of success in performing such methods (given the detailed treatment guidance provided). With further regard to the recitation in c) of claim 1 of the language “administering… based on determining that the subject is more likely to respond to treatment and/or likely to have a longer overall survival”, it is noted that this language does not impart any kind of manipulative difference to what is claimed beyond the requirement for an “administering” performed “following the determining”, but rather simply adds an instructional limitation to the method suggested by the prior art; such a limitation is nonfunctional descriptive material that is not given patentable weight when comparing the claimed invention to the prior art (and furthermore, Formica et al suggests the increased likelihood of survival associated with rs699947 A/A and A/C relative to C/C, as discussed above).
Regarding dependent claim 5, Formica et al disclose the use of patient blood samples in genotyping (see page 144, right column, particularly the third full paragraph, and page 145, both columns). Regarding dependent claim 6, Formica et al teach the alternative of PCR (followed by sequencing) sequencing, such that PCR is disclosed (see page 145, right column). Regarding claims 7-8, as these claims encompass further limitation of what is indicated as a result of the method step of “determining, based on identifying…”, the claims are obvious at least to the extent that they are directed to the embodiment of what is determined with regard to likelihood of response and/or overall survival (as this does not result in any manipulative difference in what is claimed). (With regard to such “wherein” clauses, it is noted that claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed; see MPEP 2111.04). It is also noted that Formica et al do teach administration of fluorouracil-leucovorin-irinotecan (FOLFIRI) (page 144, right column). Regarding claims 9 and 21, Formica et al teach administering bevacizumab as required by the claims (see page 144, right column, 4th full paragraph). Regarding claims 12-14, these claims recite “wherein” clauses that correspond to properties indicated by the result of the “identifying” of claim 1, rather than setting forth any type of required further action/manipulation (or any required further limitation of a structure, etc., as would be necessary for the “wherein” clause to limit what is claimed [see MPEP 2111.04]). Claim 16 similarly recites “wherein” clauses setting forth properties that a subject “will have” as a result of an outcome of the “identifying” of claim 1 “when treated with bevacizumab and fluoropyrimidine-based chemotherapy”, etc. (i.e., a type of treatment taught by Formica et al), such that Formica et al suggest all concrete/active method steps actually required by the claim language.
Regarding independent claims 3-4, Formica et al disclose treating subjects with a combination of bevacizumab and fluorouracil-leucovorin-irinotecan (FOLFIRI), and thus disclose a drug “combination therapy” meeting the requirements of each of these claims (see page 144, “Patients and methods”, bottom of left column and right column).
These claims as amended – like claim 1 – are directed to methods of treating a subject having mCRC comprising identifying in a sample obtained from the subject rs1799969 G/A and/or rs699947 A/A; claim 3 further requires administering a therapy of the type specified in claim 1 “following the identifying”, while claim 4 further requires such an administering “based on the identification of a)” (such that the administering follows the identifying). These claims thus require a combination of steps as discussed above with regard to claim 1, and are obvious for the same reasons given above with regard to that claim; it is reiterated that the claims only require one of rs1799969 and rs699947.
Claim(s) 5, 9, 18, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Papachristos et al as applied to claims 1-4, 6-8, 12-16, and 19, above, and further in view of Formica et al.
The teachings of Papachristos et al are set forth above. As Papachristos et al do not teach what type of biological material from subjects was employed in their genotyping, they do not suggest methods meeting all requirements of dependent claims 5 and 18. Furthermore, Papachristos et al do not provide details with regard to dosages/administration of bevacizumab, and thus do not teach all limitations of claims 9 and 21.
Formica et al, like Papachristos et al, teach methods in which genotyping - including of rs699947 - is performed on subjects being treated mCRC with a combination of bevacizumab and a fluoropyrimidine (specifically fluorouracil, in the combination FOLFIRI); see entire reference, particularly the Abstract, and pages 144-145, including Table 1 (particularly the first entry).
With particular regard to claims 5 and 18, Formica et al disclose the use of patient blood samples in genotyping, further teaching that such samples were stored at -80oC (see page 144, right column, particularly the third full paragraph, and page 145, both columns). In view of the teachings of Formica et al, 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 employed whole blood (as taught by Formica et al) in the genotyping of Papachristos et al, and thereby to have performed a method meeting all of the requirements of claims 5 and 18. First, an ordinary artisan would have recognized that any convenient source of patient DNA, and particularly blood as taught by Formica et al - given the ease of storage taught by Formica et al, as well as the ease and convenience of obtaining this widely-used sample type - could be employed successfully in the methods suggested by Papachristos et al. Second, given Papachristos et al’s failure to disclose the source of genetic material they employed in their genotyping, an ordinary artisan would have looking to the teachings of the prior art for guidance regarding sample types that have been used successfully in methods such as those taught by Papachristos et al, and in doing so would have readily identified prior art teachings regarding the use of blood in such testing, as exemplified by Formica et al. Thus, the use of blood in the genotyping of Papachristos et al would have been obvious to one of ordinary skill in the art, for multiple reasons.
With particular regard to claims 9 and 21, Formica et al disclose administering bevacizumab at 5 mg/kg via intravenous infusion, in 2 week cycles (see page 144, right column, 4th full paragraph). In view of the teachings of Formica et al, 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 employed in the methods suggested by Papachristos et al an administering of bevacizumab as detailed by Formica et al, and thereby to have performed a method meeting the requirements of claims 9 and 21. Given the lack of specific guidance provided by Papachristos et al, an ordinary artisan would have been motivated to have made such a modification simply for the benefit of successfully treating subjects/patients (via the use of a known treatment protocol).
It is noted that the Reply filed September 29, 2025 traverses prior rejections based upon the Papachristos et al reference, the Formica et al reference, and the combination thereof (see Reply at pages 14-16). While these arguments have been reviewed and considered, the amended claims are now rejected on the grounds set forth above, and Applicant’s arguments are not found persuasive with regard to the current rejections applied to the amended claims. It is particularly noted that the current rejections address the new claim limitations requiring a more particular order of steps (and specifically an “administering” following the other recited steps).
Conclusion
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/DIANA B JOHANNSEN/Primary Examiner, Art Unit 1682