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 .
Election/Restrictions
Applicant’s election without traverse of Group I, ERCC2 (NER gene), prostate cancer in the reply filed on 12/21/2025 is acknowledged.
Claims 13-14 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/21/2025.
Priority
The instant application was filed 05/18/2023 and is a continuation of PCT/US2021/072496 , filed 11/18/2021; which claims priority from provisional application 63115580 , filed 11/18/2020; claims priority from provisional application 63127102 , filed 12/17/2020 and claims priority from provisional application 63223540 , filed 07/19/2021.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119 (e0, 35 U.S.C. 120, 121, 365(c), or 386(c) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No 63127102 , and application 63223540, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The cited applications do not recite ERCC2 and thus do not provide support for any claims which require ERCC2.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 5/18/2023 is being considered by the examiner.
Specification
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required: Claims 47-48, 51, 53-54 recite, “threshold transcription level.” Review and searching of the specification did not reveal antecedent basis for this limitation.
Claim Objections
Claims 1, 4-12, 15, 44-63 are objected to because of the following informalities:
Claims 1, 44, , 51, 57 recite, “HydroxyUreaMethylAcylfulvene.” This is not a proper noun and thus does not need to be capitalized. Further the art teaches, “hydroxyurea methylacylfulvene.”
Claim 11 is objected to as it recites “BRCA1, BRCA2, ATM, ATR, ERCC2, ERCC3, ERCC4, ERCC5, ERCC6, FANCD2, RAD51, or PALB2” but does not recite the full terminology for the acronym (or abbreviation). Claims are more concise when the first time an acronym (or abbreviation) is presented the full terminology is also presented. Finally an acronym (or abbreviation) may have alternative meanings to an artisan.
Claim 12 is objected to as it recites “RPA1, FANCE, FANCL, ERCC8/CSA, BRIP1, FANCF, MRE11A, BLM, ERCC3/XPB, FANCM, FANCB, CHEK1, FANCI, ATM, ERCC4/XPG, ERCC6/CSB, CHEK2, ERCC2/XPD, or ERCC3” but does not recite the full terminology for the acronym (or abbreviation). Claims are more concise when the first time an acronym (or abbreviation) is presented the full terminology is also presented. Finally an acronym (or abbreviation) may have alternative meanings to an artisan.
Claim 44, 51, 57 is objected to as it recites “ERCC2” but does not recite the full terminology for the acronym (or abbreviation). Claims are more concise when the first time an acronym (or abbreviation) is presented the full terminology is also presented. Finally an acronym (or abbreviation) may have alternative meanings to an artisan.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 4-12, 44-63 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
As set forth in In re Alonso 88 USPQ2d 1849 (Fed. Cir. 2008), at 1851:
The written description requirement of 35 U.S.C. § 112, ¶ 1, is straightforward: “The specification shall contain a written description of the invention ….” To satisfy this requirement, the specification must describe the invention in sufficient detail so “that one skilled in the art can clearly conclude that the inventor invented the claimed invention as of the filing date sought.” Lockwood v. Am. Airlines, Inc., 107 F.3d 1565, 1572 [41 USPQ2d 1961] (Fed. Cir. 1997); see also LizardTech, Inc. v. Earth Res. Mapping, Inc., 424 F.3d 1336, 1345 [76 USPQ2d 1724] (Fed. Cir. 2005); Eiselstein v. Frank, 52 F.3d 1035, 1039 [34 USPQ2d 1467] (Fed. Cir. 1995).
Alonso at 1852:
A genus can be described by disclosing: (1) a representative number of species in that genus; or (2) its “relevant identifying characteristics,” such as “complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics.” Enzo, 323 F.3d at 964.
In applying the test as set forth in Alonso, it is noted that applicant is claiming in independent claim 1: ) A method for determining sensitivity of a cancer to an anti-cancer agent, comprising determining an expression level of at least one biomarker, an expression level of at least one gene associated with DNA repair, a transcription level of at least one thereof, or any combination thereof, wherein the anti-cancer agent comprises HydroxyUreaMethylAcylfulvene, and wherein a reduced expression or transcription level compared to a standard or control sample indicates a sensitivity of the cancer to HydroxyUreaMethylAcylfulvene.
Thus the claim encompasses any sample from any species from any tissue or fluid. Further it encompasses any species and any cancer. Further it encompasses anything which can be considered a gene associated with DNA repair, and anything which can broadly be encompassed by a standard or control sample.
Independent claim 44 is drawn to A method for determining sensitivity of a prostate cancer to HydroxyUreaMethylAcylfulvene, comprising:(a) determining, in a biological sample comprising prostate cancer cells, a transcription level of ERCC2, wherein ERCC2 is a nucleotide excision repair gene; and(b) comparing the transcription level of ERCC2 to a transcription level of ERCC2 in a standard or control sample,wherein a reduced transcription level of ERCC2 relative to the standard or control sample indicates sensitivity of the prostate cancer to HydroxyUreaMethylAcylfulvene.
The claim encompass anything broadly encompasses by a standard or any control sample.
Independent claim 51 is drawn to a method for determining whether a prostate cancer specimen is sensitive to HydroxyUreaMethylAcylfulvene, comprising: (a) determining a transcription level of ERCC2 mRNA in the prostate cancer specimen, wherein ERCC2 is a nucleotide excision repair gene; b) comparing the transcription level of ERCC2 mRNA to a threshold transcription level; and (c) identifying the prostate cancer specimen as sensitive to HydroxyUreaMethylAcylfulvene when the transcription level of ERCC2 mRNA is lower than the threshold transcription level.
The claim encompass anything broadly encompasses by a standard or any control sample.
Independent claim 57 is drawn to A method for determining sensitivity of a prostate cancer in a subject to HydroxyUreaMethylAcylfulvene, comprising: (a) determining a transcription level of ERCC2 mRNA in a cancer sample from the subject, wherein ERCC2 is a nucleotide excision repair gene; (b) determining a transcription level of ERCC2 mRNA in a control sample; (c) comparing the transcription levels; and (d) determining that the prostate cancer is sensitive to HydroxyUreaMethylAcylfulvene when the transcription level of ERCC2 mRNA in the cancer sample is reduced relative to the transcription level of ERCC2 mRNA in the control sample.
Thus the claim encompasses any sample from any species from any tissue or fluid. Further it encompasses any species and any cancer. Further it encompasses anything which can be considered a gene associated with DNA repair, and anything which can broadly be encompassed by a standard or control sample.
All the independent claims are drawn to transcription level. However, the teachings of specification with respect to expression level of NER genes in cancer is example 11, 0082 which teaches the use of The Cancer Genome Atlas, which provides mRNA levels not transcription levels. Cheadle (Ann N Y Acad Sci. 2005 Nov:1058:196-204.) teaches, “Standard techniques measure changes in total cellular poly(A) mRNA levels. The assumption that changes in gene expression as measured by these techniques are directly and well correlated with changes in rates of new gene synthesis form the basis of attempts to connect coordinated changes in gene expression with shared transcription regulatory elements. Yet systematic attempts at this approach remain difficult to demonstrate convincingly. One reason for this difficulty may result from the intricate convergence of both transcriptional and mRNA turnover events which, together, directly influence steady-state mRNA levels. Recent technical advances have led to the successful scale-up and application of nuclear run-on procedures directly to microarrays. This development has allowed a gene-by-gene comparison between new gene synthesis in the nucleus and measured changes in total cellular polyA mRNA. Results from these studies have begun to challenge the strict interpretation of changes in gene expression measured by conventional microarrays as being closely correlated with changes in mRNA transcription rate, but rather they tend to support the significant expansion of the role played by changes in mRNA stability regulation to standard analyses of gene expression. “ Thus the claims lack adequate written description from the breadth of the claims
The teachings of specification with respect to expression level of NER genes in cancer is example 11, 0082 which teaches the use of The Cancer Genome Atlas from glioblastoma. The specification provides no specific teaching with respect to ERCC2 expression in prostate cancer. Kellner (Cancer Res 1987;47:3186-3189) teaches, “.Myeloid and T-lymphocyte leukemia cells were most sensitive (50% inhibitory concentration,6-11 IIM).but B-cell leukemia/lymphoma, melanoma, and ovarian carcinoma cells were at least 10 times more resistant,”
The art of Cheung et al (Nature Genetics, 2003, volume 33, pages 422-425) teaches that there is natural variation in gene expression among different individuals. The reference teaches an assessment of natural variation of gene expression in lymphoblastoid cells in humans, and analyzes the variation of expression data among individuals and within individuals (replicates) p.422, last paragraph; Fig 1). The data indicates that, for example, expression of ACTG2 in 35 individuals varied by a factor of 17; and that in expression of the 40 genes with the highest variance ratios, the highest and lowest values differed by a factor of 2.4 or greater (Fig 3).
Saito-Hisaminato et al. (DNA research (2002) volume 9, pages 35-45) teaches that gene expression is not predictable across different human tissues. Thus the use of any sample and/or any control or standard would not provide predictable results as genes are differentially expressed in different tissues.
Benner et al (Trends in Genetics (2001) volume 17, pages 414-418) teaches that, “Here, the ‘homology-implies-equivalency’ assumption is restricted to a subset of homologs that diverged in the most-recent common ancestor of the species sharing the homologs. This strategy is useful, of course. But it is likely to be far less general than is widely thought. Two species living in the same space, almost by axiom, cannot have identical strategies for survival. This, in turn, implies that two orthologous proteins might not contribute to fitness in exactly the same way in two species” (see page 414, 3rd column last full paragraph). Benner specifically describes that although the leptin gene homologs have been found in mice and humans, their affect is different (see page 414, 3rd column last paragraph-3rd column page 415). Benner specifically teaches that the leptin gene in mice plays a major role in obesity, but no such effect has been demonstrated in humans due perhaps to the different evolutionary forces. Benner thus teaches that the activity and function of genes in different species is unpredictable. Further description of differential expression of ERCC2 in human glioblastoma does not provide adequate written description for any cancer, any sample, any threshold and/or any control sample or standard for the detection of sensitivity to HydroxyUreaMethylAcylfulvene. Further the claims encompass any genes which can broadly be interpreted as a gene associated with DNA repair, which encompasses an enormous genus of genes in any species, however the teachings of the specification are limited to human genes recited in the claims which is not commensurate in scope with the genus of claim 1.
New matter
MPEP 2163 IB New or amended claims section II
With respect to newly added or amended claims, applicant should show support in the original disclosure for the new or amended claims. See, e.g., Hyatt v. Dudas, 492 F.3d 1365, 1370, n.4 (Fed. Cir. 2007) (citing MPEP § 2163.04 which provides that a "simple statement such as ‘applicant has not pointed out where the new (or amended) claim is supported, nor does there appear to be a written description of the claim limitation ‘___’ in the application as filed’ may be sufficient where the claim is a new or amended claim, the support for the limitation is not apparent, and applicant has not pointed out where the limitation is supported."); see also MPEP §§ 714.02 and 2163.06 ("Applicant should ... specifically point out the support for any amendments made to the disclosure."); and MPEP § 2163.04
Claim 55 has been added by amendment and recites, “wherein identifying the prostate cancer specimen as sensitive comprises determining that the ratio is less than 1.” The response does not indicate where support for the amendment can be found. The originally filed claims did not support this amendment. Review and searching of the specification did not reveal support for this amendment. Thus the amendment appears to be new matter.
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, 4-12, 15, 44-50 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is indefinite because it lacks a positive active step relating back to the preamble. The preamble recites a method for determining sensitivity of a cancer to an anti-cancer agent, however the last positive active step is drawn to determining an expression level of at least one biomarker, an expression level of at least one gene associated with DNA repair, a transcription level of at least one thereof, or any combination thereof. Therefore it is unclear as to whether the method is drawn to determining sensitivity of a cancer to an anti-cancer agent or determining an expression level of at least one biomarker, an expression level of at least one gene associated with DNA repair, a transcription level of at least one thereof, or any combination thereof. The metes and bounds are unclear if expression is in a cancer sample, cancer cell treated with the anti-cancer, or something else.
Claim 4 recites, “wherein a reduced expression or transcription level compared to a standard or control sample indicates a sensitivity of the cancer to the anti-cancer agent.” However independent claim 1 recites, “wherein a reduced expression or transcription level compared to a standard or control sample indicates a sensitivity of the cancer to HydroxyUreaMethylAcylfulvene.” Thus the metes and bounds are unclear how claim 4 further limits the independent claim.
Claim 11 recites, “at least one gene associated with DNA repair comprises BRCA1, BRCA2, ATM, ATR, ERCC2, ERCC3, ERCC4, ERCC5, ERCC6, FANCD2, RAD51, or PALB2.” The metes and bounds are unclear what other alternatives are intended to be encompassed by the claim. See In re Kiely, 2022 USPQ2d 532 at 2* (Fed. Cir. 2022)
Claim 12 recites, “at least one biomarker comprises expression of RPA1, FANCE, FANCL, ERCC8/CSA, BRIP1, FANCF, MRE11A, BLM, ERCC3/XPB, FANCM, FANCB, CHEK1, FANCI, ATM, ERCC4/XPG, ERCC6/CSB, CHEK2, ERCC2/XPD, or ERCC3.” The metes and bounds are unclear what other alternatives are intended to be encompassed by the claim. See In re Kiely, 2022 USPQ2d 532 at 2* (Fed. Cir. 2022)
Claim 44 is indefinite because it lacks a positive active step relating back to the preamble. The preamble recites a method for determining sensitivity of a prostate cancer to HydroxyUreaMethylAcylfulvene, however the last positive active step is drawn to comparing the transcription level of ERCC2 to a transcription level of ERCC2 in a standard or control sample. Therefore it is unclear as to whether the method is drawn to for determining sensitivity of a prostate cancer to HydroxyUreaMethylAcylfulvene or comparing the transcription level of ERCC2 to a transcription level of ERCC2 in a standard or control sample.
Claim 44 recites, “determining, in a biological sample comprising prostate cancer cells, a transcription level of ERCC2, wherein ERCC2 is a nucleotide excision repair gene.” Claim 45 recites, “wherein determining the transcription level of ERCC2 comprises measuring an amount of mRNA transcribed from ERCC2.” Claim 44 thus appears to require determination of a transcription level, which is done by nuclear run-on experiments. However, claim 45 appears to be an attempt to define transcription level as amount of mRNA. The specification in example 11 teaches the use of THE Cancer Genome Atlas which provides expression levels of mRNA. Thus the metes and bounds are unclear if the claims are drawn to examination of transcription by nuclear run-on as the literal reading of the claim suggest or mRNA levels as dependent claims and specification suggest.
Claim 50 recites, “wherein the reduced transcription level comprises a reduced amount of ERCC2 mRNA relative to the standard or control sample.” However claim 44 recites, “a reduced transcription level of ERCC2 relative to the standard or control sample indicates sensitivity of the prostate cancer to HydroxyUreaMethylAcylfulvene.” Thus it is unclear how claim 50 further limits claim 44 as it appears to merely restates a limitation of the independent claim.
Claims 61 recites, “determining that the prostate cancer is sensitive comprises determining that the ratio is below a threshold ratio.” The metes and bounds are unclear what a threshold ratio requires as the claim does not define the term. The specification does not recite or define the term. “threshold ratio “ is anot an art accepted term. Thus the metes and bounds are unclear.
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, 4-12, 15, 44-63 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural correlation and mental step without significantly more in the absence of a deletion of the recited markers or underexpression of the recited markers. The claim(s) recite(s) the abstract idea or mental step of comparing. Further the claim has been amended to recite, “wherein a favorable outcome is expected if the nucleic acid is deleted or underexpressed “ which is a natural law or correlation. This judicial exception is not integrated into a practical application because if there is no deletion or an amplification or unchanged expression or increased expression no treatment step is required. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because if there is no deletion or an amplification or unchanged expression or increased expression no treatment step is required.
Claim analysis
The instant claim 1 is directed towards A method for determining sensitivity of a cancer to an anti-cancer agent, comprising determining an expression level of at least one biomarker, an expression level of at least one gene associated with DNA repair, a transcription level of at least one thereof, or any combination thereof, wherein the anti-cancer agent comprises HydroxyUreaMethylAcylfulvene, and wherein a reduced expression or transcription level compared to a standard or control sample indicates a sensitivity of the cancer to HydroxyUreaMethylAcylfulvene.
The claim does not require a sample thus the determining expression broadly encompasses reading a report or database as done in example 11 of the specification. The correlation in the wherein clause in a natural correlation or phenomena. The determination of a reduction requires a comparison which is a mental step or abstract idea.
Independent claim 44 is drawn to A method for determining sensitivity of a prostate cancer to HydroxyUreaMethylAcylfulvene, comprising:(a) determining, in a biological sample comprising prostate cancer cells, a transcription level of ERCC2, wherein ERCC2 is a nucleotide excision repair gene; and(b) comparing the transcription level of ERCC2 to a transcription level of ERCC2 in a standard or control sample, wherein a reduced transcription level of ERCC2 relative to the standard or control sample indicates sensitivity of the prostate cancer to HydroxyUreaMethylAcylfulvene.
The correlation in the wherein clause in a natural correlation or phenomena. The comparing step is a mental step or abstract idea.
Independent claim 51 is drawn to A method for determining whether a prostate cancer specimen is sensitive to HydroxyUreaMethylAcylfulvene, comprising: (a) determining a transcription level of ERCC2 mRNA in the prostate cancer specimen, wherein ERCC2 is a nucleotide excision repair gene; b) comparing the transcription level of ERCC2 mRNA to a threshold transcription level; and (c) identifying the prostate cancer specimen as sensitive to HydroxyUreaMethylAcylfulvene when the transcription level of ERCC2 mRNA is lower than the threshold transcription level.
The comparing step is a mental step or abstract idea. The identifying step is a mental step or abstract idea and a natural correlation or natural phenomenon.
Independent claim 57 is drawn to A method for determining sensitivity of a prostate cancer in a subject to HydroxyUreaMethylAcylfulvene, comprising: (a) determining a transcription level of ERCC2 mRNA in a cancer sample from the subject, wherein ERCC2 is a nucleotide excision repair gene; (b) determining a transcription level of ERCC2 mRNA in a control sample; (c) comparing the transcription levels; and (d) determining that the prostate cancer is sensitive to HydroxyUreaMethylAcylfulvene when the transcription level of ERCC2 mRNA in the cancer sample is reduced relative to the transcription level of ERCC2 mRNA in the control sample.
The comparing step is a mental step or abstract idea. The determining step is a mental step or abstract idea and a natural correlation or natural phenomenon
The measuring or determining the amount of a nucleic acid or transcription level in claims 44, 51, and 57 is considered to be an active step requiring the analysis of a sample.
Dependent claims set forth further limitations to about the reference level, threshold level, sample , subject and type of cancer.
According to the 2019 Patent Eligibility Guidance an initial two step analysis is required for determining statutory eligibility.
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter? In the instant case the Step 1 requirement is satisfied as the claims are directed towards a process.
Step 2A Prong one. Do the claims encompass a law of nature, a natural phenomenon or an abstract idea? Yes the independent claims encompass abstract idea/mental step and law of nature or natural phenomena.
With regards to claim 1, the claim recites, “determining an expression level of at least one biomarker, an expression level of at least one gene associated with DNA repair, a transcription level of at least one thereof, or any combination thereof, wherein the anti-cancer agent comprises HydroxyUreaMethylAcylfulvene, and wherein a reduced expression or transcription level compared to a standard or control sample indicates a sensitivity of the cancer to HydroxyUreaMethylAcylfulvene.” This is an abstract idea or mental step and natural correlation
Claim 44 recites, “comparing the transcription level of ERCC2 to a transcription level of ERCC2 in a standard or control sample, wherein a reduced transcription level of ERCC2 relative to the standard or control sample indicates sensitivity of the prostate cancer to HydroxyUreaMethylAcylfulvene.” This is an abstract idea or mental step and natural correlation
Claim 51 recites. “; b) comparing the transcription level of ERCC2 mRNA to a threshold transcription level; and (c) identifying the prostate cancer specimen as sensitive to HydroxyUreaMethylAcylfulvene when the transcription level of ERCC2 mRNA is lower than the threshold transcription level. .” This is an abstract idea or mental step and natural correlation
Claim 57 recites, “c) comparing the transcription levels; and (d) determining that the prostate cancer is sensitive to HydroxyUreaMethylAcylfulvene when the transcription level of ERCC2 mRNA in the cancer sample is reduced relative to the transcription level of ERCC2 mRNA in the control sample.” This is an abstract idea or mental step and natural correlation
Step 2A prong two. Does the claim recite additional elements that integrate the judicial exception into a practical application? The answer is no as the claims provide no active steps which depend from or otherwise integrate the judicial exception.
Step 2B. Does the claim recite additional elements that are significantly more then the judicial exceptions? No, the claims provide no steps which provide specific reagents or combination of steps which provide for significantly moe as the only active steps are determining levels of mRNA.
The independent claim merely requires determining the expression level. . The specification teaches:
[0082] Example 11: Prediction of LP-184 sensitivity based on NER gene expression [0083] The expression level of the following NER genes were able to classify the top 15 predicted sensitive and top 15 predicted insensitive Glioblastoma (GBM) tumor sample records into distinct sensitivity groups out of a total of 166 records from TCGA (The Cancer Genome Atlas), whereas parameters such as gender and race could not classify the samples. The genes include: POLE2, RFC3, POLE, LIG1, PARP2, RFC5, LIG3, RFC4, INO80B, POLR2F, PCNA, ACTR5, POLD1, GPS1, NFRKB, XAB2, POLRD2, POLD3, INO80E, ZNF830, ERCC4, ERCC8, POLE3, RPA2, GTF2H4, PARP1, ERCC3, POLR2B, RUVBL1, MCRS1, USP45, COPS5, POLR2I, COPS3, UBE2N, INO80D, PRPF19, COPS7B, XRCC1, ERCC6, UBE2I, POLR2E, CCNH, ACTR8, USP7, POLR2G, UBB, ERCC5, INO80C, RPA1, POLR2J, UBE2V2, POLR2H, RPA3, AQR, RFC1, PPIE, POLD2, ERCC2, POLE4, SUMO4, COPS4, YYI, RAD23A, COPS6, XPA, MNATI, POLR2K, RAD23B, CUL4B, POLR2A, PIAS1, ISYI, GTF2H5, POLK, EP300, UBA52, XPC, ERCC1, RBX1, RNF111, TCEA1, GTF2H3, CUL4A, INO80, COPS7A, COPS8, RPS27A, PIAS3, TFPT, GTF2H2, CETN2, SUMO3, CHDIL, GTF2H1, COPS2, UBC, CDK7, ACTB, POLR2L, ELL, DDB2, POLD4in different cases or, for instance in different chronic diseases or patient populations.
Thus the claims encompass reading a report or database. Further McMorris(J. Org. Chem. 2001, 66, 6158-616), Kulkami (Cancer Res (2019) 79 (13_Supplement): 4789.) Kellner (Biochemical Pharmacology. Vol. 48, No. 2, pp. 403-409, 1994), Liu (Journal of Cancer (2018; 9(16): 2786-2794) demonstrate the active steps are routine and conventional.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 1, 4-12, 44-63 is/are rejected under 35 U.S.C. 103 as being unpatentable over McMorris(J. Org. Chem. 2001, 66, 6158-616), Kulkami (Cancer Res (2019) 79 (13_Supplement): 4789.) Kellner (Biochemical Pharmacology. Vol. 48, No. 2, pp. 403-409, 1994), Liu (Journal of Cancer (2018; 9(16): 2786-2794)
As indicated above the teachings of the specification are limited to LP-184 which is LP-184 HydroxyUrea MethylAcylfulvene. The specification teaches, “[0028] The term illudin also may include HydroxyUreaMethylAcylfulvene, (LP184).” Thus any teachings with respect to LP184, LP-184, 184 HydroxyUrea MethylAcylfulvene appear to be directed to the compound of the claim.
Further the claims recite, ”transcription level.” However the only teaching with respect to expression level are in example 11 with respect to 0082 and 0083 are limited to TCGA which provides mRNA levels. Thus the broadest reasonable interpretation of transcription level, consistent with the specification is mRNA levels.
McMorris teaches,” IIlludins and certain derivatives have been evaluated for antitumor activity in the National Cancer Institute Developmental Therapeutics Program. Illudin M signifi cantly increased the life span of rats with Dunning leukemia, but had a low therapeutic index in solid tumor systems.4 In contrast, we have found derivatives of illudins, including hydroxymethylacylfulvene.” (2nd paragraph introduction) McMorris teaches, “The illudins and acylfulvenes also differ from other agents with alkylating activity in their preferential cytotoxicity toward cell lines deficient in the excision repair cross-complementing (ERCC) DNA repair enzymes ERCC2 and ERCC3, which indicates that the repair of irofulven-induced DNA damage requires a full complement of DNA repair mechanisms that may be absent in sensitive cell lines..” (6158, bottom 2nd column, top of page 6159).
McMorris does not specifically teach determining mRNA expression or transcription of ERCC2.
However, Kulkami teaches, “LP-184 is a next-generation analog of Irofulven with broad anti-tumor activity that counteracts multi-drug resistance pathways and is potentially synergistic with many classes of anticancer agents” (abstract) Kulkami teaches, “. Lantern Pharma has developed a technology platform termed RADRTM that can be used to construct responder/ non-responder profiles based on gene expression signatures and predict true responders before conducting a clinical trial in order to achieve higher success rates. RADRTM is an Al-based machine learning approach for candidate biomarker identification and patient stratification. RADRTM is a combination of three automated modules working sequentially to generate drug- and tumor-specific gene signatures predictive of response. RADRTM emphasizes the integration of biological knowledge, data-driven feature selection, and robust Al algorithms to derive biomarkers in a hypothesis-free manner. In analytic demonstrations, RADRTM was able to achieve an average accuracy of 85% in validation tests using preclinical datasets associated with selected solid tumor indications and approved drugs. As part of RADRTM drug model building and development, we used a dataset showing preclinical efficacy of our pipeline oncology candidate LP-184. We obtained baseline cell line gene expression profiles covering more than 18,000 transcripts per cell line and corresponding LP-184 sensitivity records from the NCI60 cancer cell line panel. Using RADRTM, we derived a panel of 10 genes whose expression levels are predictive of overall response at an accuracy of 100%. Thus, RADRTM was able to identify the top 10 genes for prediction of either drug sensitivity or insensitivity, demonstrating the hypothesis-free identification of biomarkers with biological relevance and statistical rigor and having highest possible prediction accuracy. Genes from the final 10 predictive list were found to be functionally involved in LP-184-specific induction of bioactivation and are in agreement with its mechanism of action. These preliminary biomarker analyses will be further validated using LP-184 sensitivity and pre-treatment gene expression data derived from ex vivo models of fresh prostate tumor biopsy samples.”
Further Kelner teaches, “Expression of ERCC2 in the ST4-12 strain conferred resistance to illudin S as measured by both the 4%hr (continuous exposure) screening assay and coIony-forming assays (Figs. 1 and 2, and Table 2), confirming that the ERCC2 DNA repair protein was critical to the repair of illudin damage.”
Liu teaches, “Thus, it seems that deficiency in the DNA repair gene ERCC2 and ERCC5 are thought to have a central role in the modulation of PCa susceptibility.” (2972, 2nd column, bottom).
As noted in the MPEP 2111.02, “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction.” Further, a preamble is generally not accorded any patentable weight where it merely recites the purpose of a process or the intended use of a structure, and where the body of the claim does not depend on the preamble for completeness but, instead, the process steps or structural limitations are able to stand alone. See In re Hirao, 535 F.2d 67, 190 USPQ 15 (CCPA 1976) and Kropa v. Robie, 187 F.2d 150, 152, 88 USPQ 478, 481 (CCPA 1951). Accordingly, the claim language of "a method for determining sensitivity of a cancer to an anti-cancer agent” merely sets forth the intended use or purpose of the claimed methods, but does not limit the scope of the claims.
MPEP 2106 states: Claim scope is not limited by claim language that
suggests or makes optional but does not require steps to be performed, or
by claim language that does not limit a claim to a particular structure.
However, examples of claim language, although not exhaustive, that may
raise a question as to the limiting effect of the language in a claim are:
(A) “ adapted to ” or “adapted for ” clauses;
(B) “ wherein ” clauses; and
(C) “ whereby ” clauses.
The determination of whether each of these clauses is a limitation in a claim
depends on the specific facts of the case. In Hoffer v. Microsoft Corp., 405
F.3d 1326, 1329, 74 USPQ2d 1481, 1483 (Fed. Cir. 2005), the court held that
when a “whereby’ clause states a condition that is material to patentability,
it cannot be ignored in order to change the substance of the invention.” Id.
However, the court noted (quoting Minton v. Nat ’l Ass ’n of Securities
Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003))that a “whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” Id.<
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior the effective filing date of the claims to determine expression of ERCC2 in cancer cells from the subject and compare to expression in non-cancer cells the subject. The artisan would be motivated to examine if ERCC2 expression is different between cancer and non-cancer cells from a subject. The artisan would have a reasonable expectation of success as the artisan is merely detecting a known gene in known samples. (claims 1 and 4)
With regards to claim 5, prostate cancer is a solid tumor.
With regards to claims 6-7, Kulkami and Liu teach prostate cancer.
With regards to claims 9-12, the cited prior art teaches detection of ERCC2.
As noted in the MPEP 2111.02, “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction.” Further, a preamble is generally not accorded any patentable weight where it merely recites the purpose of a process or the intended use of a structure, and where the body of the claim does not depend on the preamble for completeness but, instead, the process steps or structural limitations are able to stand alone. See In re Hirao, 535 F.2d 67, 190 USPQ 15 (CCPA 1976) and Kropa v. Robie, 187 F.2d 150, 152, 88 USPQ 478, 481 (CCPA 1951). Accordingly, the claim language of " method for determining sensitivity of a prostate cancer to HydroxyUreaMethylAcylfulvene” merely sets forth the intended use or purpose of the claimed methods, but does not limit the scope of the claims.
MPEP 2106 states: Claim scope is not limited by claim language that
suggests or makes optional but does not require steps to be performed, or
by claim language that does not limit a claim to a particular structure.
However, examples of claim language, although not exhaustive, that may
raise a question as to the limiting effect of the language in a claim are:
(A) “ adapted to ” or “adapted for ” clauses;
(B) “ wherein ” clauses; and
(C) “ whereby ” clauses.
The determination of whether each of these clauses is a limitation in a claim
depends on the specific facts of the case. In Hoffer v. Microsoft Corp., 405
F.3d 1326, 1329, 74 USPQ2d 1481, 1483 (Fed. Cir. 2005), the court held that
when a “whereby’ clause states a condition that is material to patentability,
it cannot be ignored in order to change the substance of the invention.” Id.
However, the court noted (quoting Minton v. Nat ’l Ass ’n of Securities
Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003))that a “whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” Id.<
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior the effective filing date of the claims to determine expression of ERCC2 mRNA in prostate cancer cells from the subject and compare to expression in non-cancer cells the subject. The artisan would be motivated to examine if ERCC2 mRNA expression is different between cancer and non-cancer cells from a subject. The artisan would have a reasonable expectation of success as the artisan is merely detecting a known gene in known samples. (claims 44-45, 57-59)
With regards to claim 46-49, McMorris teaches, “The illudins and acylfulvenes also differ from other agents with alkylating activity in their preferential cytotoxicity toward cell lines deficient in the excision repair cross-complementing (ERCC) DNA repair enzymes ERCC2 and ERCC3, which indicates that the repair of irofulven-induced DNA damage requires a full complement of DNA repair mechanisms that may be absent in sensitive cell lines..” (6158, bottom 2nd column, top of page 6159).
With regards to claim 49, prostate cancer is a solid tumor.
With regards to claim 51, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims to examine expression of ERCC2 in prostate cancer cells and prostate control cells to predict likeliness of response to illudins and acylfulvenes, including HydroxyUrea MethylAcylfulvene based on decrease expression of ERCC2 in test samples relative to controls. The artisan would be motivated as McMorris teaches, “The illudins and acylfulvenes also differ from other agents with alkylating activity in their preferential cytotoxicity toward cell lines deficient in the excision repair cross-complementing (ERCC) DNA repair enzymes ERCC2 and ERCC3, which indicates that the repair of irofulven-induced DNA damage requires a full complement of DNA repair mechanisms that may be absent in sensitive cell lines..” The artisan would have a reasonable expectation of success as methods of detecting ERCC2 was known as was the correlation of absence of ERCC2 with response to illudins and acylfulvenes.
With regards to claim 52, prostate cancer is a solid tumor.
With regards to claim 53-54,62-63 McMorris teaches, “The illudins and acylfulvenes also differ from other agents with alkylating activity in their preferential cytotoxicity toward cell lines deficient in the excision repair cross-complementing (ERCC) DNA repair enzymes ERCC2 and ERCC3, which indicates that the repair of irofulven-induced DNA damage requires a full complement of DNA repair mechanisms that may be absent in sensitive cell lines..” (6158, bottom 2nd column, top of page 6159).
The art does not specifically teach a ration of less than 1. However it would have been prima facie obvious to one of ordinary skill in the art to make of ration of the expression of ERCC2 in prostate cancer cells to normal prostate cells. The artisan would be motivated to provide a single number indicative of response to illudins and acylfulvenes, including HydroxyUrea MethylAcylfulvene.
Summary
No claims are allowed.
Conclusion
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/Steven Pohnert/ Primary Examiner, Art Unit 1683
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