FINAL ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This action is responsive to the Supplemental Response filed 28 January 2026. Claims 35, 45-46, 48, and 50-54 have been amended, and claims 35-54 remain under consideration. Applicant’s amendments and arguments have been thoroughly reviewed, and Applicant’s amendment to independent claim 35 (the only independent claim) to recite “wherein TP53 template DNA molecules having the same sequence are each uniquely labeled with a distinct UID” has overcome the following rejections set forth in the prior Office action:
The rejection of claims 35-54 under 35 USC 112(b) (given the recitation “each uniquely labeled”, which clarifies what is required);
the rejection under 35 USC 102(a)(1); and
the rejections under 35 USC 103.
Claims 35-54 remain rejected for the reasons given below, which include new grounds of rejection necessitated by Applicant’s amendments. Any rejections and/or objections not reiterated in this action have been withdrawn. This action is FINAL.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Rejections - 35 USC § 103
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.
THE FOLLOWING ARE NEW GROUNDS OF REJECTION NECESSITATED BY APPLICANT’S AMENDMENTS:
Claim(s) 35-38 and 43-54 are rejected under 35 U.S.C. 103 as being unpatentable over Yamada et al (European Journal of Obstetrics & Gynecology and Reproductive Biology 171:96 [2013]; cited in IDS) in view of Kinde et al (PNAS 103(23):9530-9535 [June 2011]; cited in IDS), as evidenced by the specification.
Instant independent claim 35 as amended is directed to a method comprising “testing ovarian cyst fluid for a mutation in TP53, wherein the step of testing employs a step of adding a unique identifier (UID) to each of a plurality of TP53 template DNA molecules in the ovarian cyst fluid”, with the claim now further stating “wherein TP53 template DNA molecules having the same sequence are each uniquely labeled with a distinct UID”.
Yamada et al teach the successful testing of ovarian cyst fluid for TP53 mutations (see entire reference, particularly the disclosure of Samples and DNA extraction on page 97, the disclosure of PCR, electrophoresis and DNA isolation and sequencing on page 98, and the Results at pages 98-99, including Figures 2 and 4 and Table 2). It is noted that, as discussed in the specification at paragraph 10, Yamada et al’s references to the p53 gene refer to TP53 as recited in the claims, i.e., these two terms are referring to the same gene; thus, the teachings of the specification establish that it is an inherent feature of the Yamada et al reference that it disclose testing ovarian cyst fluid for mutations in TP53. Among the types of sample disclosed by Yamada et al as including a TP53 mutation is a sample of ovarian cyst fluid from a mucinous cystic tumor, i.e., a non-type II tumor (as evidenced by the teachings of the specification at paragraph 7); see page 98, left paragraph through page 99 ( “Results”), Figure 1 and Figure 2B. Yamada et al thus teach methods comprising “testing ovarian cyst fluid for a mutation in TP53”. However, with regard to the amended “wherein” clause of claim 35, while Yamada et al disclose the use of different primer pairs for amplification of each of exons 4-9 of the p53 gene, with each of these primers inherently functioning as a type of unique identifier with respect to the template it identifies (as the sequence of each primer may be used to identify the corresponding exon template and any amplification products thereof, and also to differentiate one exon and corresponding exon amplification product from any other exon/corresponding exon amplification product; see the primer sequences taught at Table 1 on page 97, and the evidence of amplification depicted in Figure 1), Yamada et al do not teach the requirement of amended claim 35 “wherein TP53 template DNA molecule shaving the same sequence are each uniquely labeled with a distinct UID”. It is also noted that Yamada et al disclose a fairly labor and time intensive process for mutation detection that includes PCR followed by gel electrophoresis, extraction of DNA from bands cut from the gel, and sequencing of extracted DNA (see page 98, sections 2.5-2.7).
Kinde et al teach an improved massively parallel sequence method, “Safe-SeqS”, that employs endogenous or exogenous UIDs (unique identifiers) and allows for both easy identification of rare mutants in population of DNA templates and determination of the number of templates analyzed and the fraction of those templates containing variant bases (see entire reference, in particular the Abstract, the “Overview” at page 9530, right column bridging to page 9531, right column, the discussion of “Exogenous UIDs” on page 9532, and the Discussion at page 9533, right column, last paragraph bridging to page 9534, top of left column). It is noted that the methods taught by Kinde et al include “assignment of a unique identifier (UID) to each DNA template molecule to be analyzed” (see again the “Overview” on page 9530, as well as the discussion of UIDs on pages 9531-9532). Kinde et al also teach that in “neoplastic diseases….the applications of rare mutant detection are manifold”, including early disease detection, detection of residual disease, and therapy monitoring (page 9530, left column, bottom of first full paragraph). Kinde et al thus disclose, in the context of a method applicable to testing for cancer-associated mutations in DNA, a step of “adding a unique identifier (UID)” of the type and in the manner now specified in claim 35.
In view of the teachings of Kinde 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 modified the methods taught by Yamada et al so as to have substituted for the testing method of Yamada et al – which as described is both time and labor intensive with regard to identifying individual variants – the Safe-SeqS sequencing methodology of Kinde et al, and thereby to have employed a testing processing employing addition of a UID as specified by Kinde et al (meeting the requirements of amended claim 35). An ordinary artisan would have been motivated to have so modified the method of Yamada et al for the benefit of allowing for more efficient detection of any present variants/ mutations (as compared to the process disclosed by Yamada et al), as well as for any of the benefits explicitly taught by Kinde et al, including the specific added benefit of determining the fraction of templates including each mutation/variant (thus better characterizing a subject’s specific disease), as well as the more general benefits pf early or residual cancer detection in an ovarian cyst fluid sample. Furthermore, given the detailed guidance provided by both Yamada et al and Kinde et al, an ordinary artisan would have had a reasonable expectation of success in performing such methods.
With further regard to dependent claim 36, which recites that “the method further comprises testing the ovarian cyst fluid for a mutation in each of at least one further gene, wherein said at least one further gene comprises KRAS”, while Yamada et al do not disclose testing ovarian fluid samples for mutations in KRAS (or other genes known to include mutations associated with ovarian neoplasms), Yamada et al do teach that mutations in KRAS (as well as other genes) is (are) known to be associated with ovarian cancers (see page 100, left column, second to last paragraph). Yamada et al state that while “p53 is only one parameter, it may be useful if it is combined with other parameters”, and that “further gene studies may contribute to establishing a new detection system for the presence of malignancies of cystic ovarian tumors” (page 100, left column, last two paragraphs). Thus, in view of Yamada 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 methods of Yamada et al’s in view of Kinde et al so as to have tested the same type of samples (i.e., ovarian cyst fluid samples) for mutations in KRAS (as well as any other genes known to exhibit mutations in association with ovarian cancer), using the same procedures suggested by Yamada et al in view of Kinde et al. An ordinary artisan would have been motivated to have made such a modification by Yamada et al’s disclosure of the relevance of KRAS mutations in ovarian cancer and explicit suggestion to conduct such further gene studies.
With further regard to dependent claims 37-38, the Safe-SeqS method as described by Kinde et al employs reagents that are target sequence specific (with TP53 being the target of the method suggested by Yamada et al in view of Kinde et al), and the UIDs corresponding to each detected target of the method of Yamada et al in view of Kinde et al are “mutation specific” in allowing detection of the specific corresponding variant/mutation (see again pages 9531-9532).
Regarding claim 43, while Yamada et al do not disclose testing for variations in TP53 other than point mutations (i.e., copy number variation and/or loss of heterozygosity as specified in the claim), Yamada et al’s teachings are sufficient to suggest testing for any variations affecting TP53, such that the teachings of Yamada et al in view of Kinde et al are sufficient to suggest what is claimed. Yamada et al disclose that other mutations and variations of TP53 are known to be associated with ovarian cancers, citing to several prior art references (page 96, right column), and - as noted above - provide motivation to identify any mutations associated with ovarian cancer (in both TP53 and other relevant genes). Thus, in view of Yamada 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 methods of Yamada et al in view of Kinde et al so as to have tested the same type of samples (i.e., ovarian cyst fluid samples) for mutations/variations of any type in TP53 (including copy number variants and loss of heterozygosity), simply for the benefit of more accurately and fully characterizing a patient’s cancer.
Regarding claim 44, it is reiterated that Yamada et al exemplify detection of point mutations in TP53; see, e.g., Figures 1-2 and 4 and Table 2 (as well as the “Results” section noted above).
Regarding the requirement of claims 45, 48, and 54 stating “wherein the ovarian cyst fluid is obtained from a type II ovarian neoplasm”, while Yamada et al do not disclose testing such fluid, Yamada et al do teach that “the most common subtype” of ovarian cancer – “high-grade serous carcinoma, is characterized by p53 mutations” (page 99, right column); thus, Yamada et al teach that their methods are relevant to analysis of high-grade serous carcinomas. The specification at page 3 discloses that such carcinomas are considered type II neoplasms, establishing that this is a property of the high-grade serous carcinomas referenced by Yamada et al. Accordingly, in view of Yamada 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 practiced the methods suggested by Yamada et al in view of Kinde et al on type II neoplasms such as high-grade serous carcinomas (again, simply because Yamada et al teach that these are “characterized by” mutations of the type analyzed by Yamada et al, making clear that the techniques of Yamada et al will prove valuable in analyzing and characterizing such cancers). With regard to further limitations of each of these claims specifying various sensitivity levels for mutation detection, MPEP 2111.04 states that:
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.
These “wherein” clauses do not impart any further requirement with respect to performance of method steps (or any particular structural limitations) – rather they state a property/characteristic of the claimed method that does not further limit the manner in which it is performed - and thus do not limit claim scope.
Regarding dependent claim 46, now reciting “wherein the ovarian cyst fluid is obtained from a non-neoplastic ovarian cyst or a benign tumor”, Yamada et al disclose performing their methods on such samples (see, e.g., the Abstract and page 97, “2.1 Participants”, and it is again noted that Kinde et al teach a benefit of mutation detection in cancer includes, e.g., identification of early “curable” disease (see page 9530, left column); thus, Yamada et al explicitly teach testing such samples, and the teachings of Yamada et al in view of Kinde et al provide further motivation to do so. Regarding the further language of this claim regarding specificity of detection, such language is (like the further “wherein” language of claims 45/48/54) not further limiting of claim scope (as the language does not impart any requirement to perform further steps, or further limit a structure, etc.; again see MPEP 2111.04).
Regarding claim 47, as Yamada et al teach that all subjects disclosed have had surgery (see page 97, left column, “Participants”), the ovarian neoplasms disclosed (including those specifically discussed above) meet the criteria of being a neoplasm that “needs surgery”; thus, Yamada et al in view of Kinde et al suggest what is claimed.
Regarding claims 49-51 (it is noted that claims 50-51 depend from claim 49), embodiments of Safe-SeqS as taught by Kinde et al include introducing UID’s via a primer (see, e.g., page 9531, left column, first full paragraph and page 9532 “Exogenous UIDs”) such that Yamada et al in view of Kinde et al suggest what is claimed.
With regard to all of claims 50-53, it is noted that amplification products including such introduced UIDs (as taught by Kinde et al) are “labeled” by those UID tags (which allow for their specific identification, tracking, etc.). Kinde et al further teach sequencing and grouping such products into families, etc. – see again pages 9531-9532, noting the disclosure of “UID families” – such that Yamada et al in view of Kinde et al suggest all required claim limitations. Regarding the further conditional/contingent limitations that apply “when a mutation is present….” (see each of claims 50-53), MPEP 2111.04(II) states: “The broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met”.
Thus, Yamada et al in view of Kinde et al suggest the methods of all of claims 35-38 and 43-54.
Claim(s) 39-41 are rejected under 35 U.S.C. 103 as being unpatentable over Yamada et al in view of Kinde et al, as evidenced by the specification, as applied to claims 35-38 and 43-54, above, and further in view of Gaspari et al (Prenatal Diagnosis 32:859 [2012]; cited in IDS).
The teachings of Yamada et al and Kinde et al (as evidenced by the specification) are set forth above. Neither Yamada et al nor Kinde et al teach the further sample types, sample collection methods, or timing of sample collection set forth in dependent claims 39-41.
Gaspari et al, like Yamada et al, disclose successfully detecting mutations in DNA obtained from ovarian cyst fluid (see entire reference). With regard to claim 39, Gaspari et al also teach performing mutation detection on ovarian cyst tissue, which constitutes a “cyst wall” sample as compared to cystic fluid (which is sufficient to meet the requirements of the claim; see page 860, right column). Given Gaspari et al’s teachings that both cyst fluid and cyst tissue may be employed successfully in analysis of mutations associated with ovarian tumors, 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 practiced the methods of Yamada et al in view of Kinde et al on either cyst fluid or cyst wall/tissue samples, or both. An ordinary artisan would have recognized such a modification as the simple substitution of one known, usable prior art sample type for another, to achieve the predictable result of detection of cancer-associated mutations of interest. Additionally or alternatively, an ordinary artisan would have been motivated to have tested both types of samples for the benefit of simply confirming results obtained with one in the other, for the benefit of ascertaining what differences are present between the two sample types (if any), or simply for the benefit of early cancer detection, as suggested by Yamada et al in view of Kinde et al.
With regard to dependent claims 40-41, Gaspari et al teach and suggest both the aspiration and testing of cystic fluid prior to any surgery (see page 860). With further regard to claim 41, it is also noted that while Yamada et al do not disclose obtaining ovarian cyst fluid prior to cyst removal, Yamada et al do suggest that the goal of establishing a detection methodology employing such fluid is detecting of ovarian cancer “without resection of the tumor tissues” (see abstract and page 97, left column), noting also that “cystic fluid is very important material for histological diagnosis with ovarian tumor without resection of ovarian tumor” (page 100, left column). Thus, in view of the teachings of Yamada et al and Gaspari 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 practiced the methods of Yamada et al in view of Kinde et al on the sample types of claims 40-41, for the benefit of determining mutation status of an ovarian cyst prior to surgery (and thus further potentially avoiding an unnecessary treatment in some patients).
Claim(s) 40 and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Yamada et al in view of Kinde et al and Gaspari et al, as evidenced by the specification, as applied to claims 40-41, above, and further in view of Troiano et al (AJR 171:1601-1605 [1998]; cited in IDS).
This rejection applies to claim 40 to the extent that it may require more particular activities related to needle aspiration of a cyst.
The teachings of Yamada et al, Kinde et al, and Gaspari et al are set forth above. None of Yamada et al, Kinde et al, and Gaspari et al teach details of needle aspiration, nor do these reference teach obtaining ovarian cyst fluid after recurrence of a cyst following removal.
Troiano et al teach obtaining ovarian cyst fluid samples using needle aspiration (see entire reference), including at least one example of performing such a method following recurrence of a cyst (see the abstract and pages 1602-1603). Troiano et al disclose that such needle aspiration may sometimes relieve symptoms in the absence of surgery (see, e.g., abstract), and also has benefits in that in can be used to treat symptoms in pregnant patients (page 1604, right column). Troiano et al also disclose that a disadvantage of needle aspiration is that “cytological examination of aspirated fluid is not enough to reliably exclude a malignancy” (as compared to surgery or biopsy, etc.) (pages 1603-1604).
In view of the teachings of Troiano 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 modified the method suggested by Yamada et al in view of Kinde et al and Gaspari et al so as to have testing ovarian cyst fluid from sources of the type disclosed by Troiano et al, including samples obtained by needle aspiration, including after recurrence (thus meeting the requirements of both claims 40 and 42). An ordinary artisan would have been motivated to have made such a modification for the benefit of obtaining and providing additional information (achieved by the testing of Yamada et al in view of Kinde et al and Gaspari et al) regarding the possibility of a cyst being or not being associated with malignancy (i.e., so as to provide additional information to patients of the type taught by Troiano et al regarding their medical condition). Further, an ordinary artisan would have been motivated to have performed such a method for the benefit of better characterizing an ovarian cyst/mass – via testing of aspirated fluid – prior to tumor resection, for the benefits of characterizing a tumor without surgical resection, and more accurately determining whether a malignancy is in fact even present (thus providing this information before taking the permanent step of ovary removal, as discussed at page 96, right column of Yamada et al).
It is noted that Applicant’s arguments pertaining to the prior rejections of claims under 35 USC 102 and 35 USC 103 have been considered to the extent that they may apply to the present rejections, however those arguments focus on a new limitation that has been addressed in the rejections now of record (and are thus non-persuasive with regard to the present rejections).
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/DIANA B JOHANNSEN/Primary Examiner, Art Unit 1682
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