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 .
This application is the national stage of PCT/US2021/062070, filed 06 December 2021, claiming priority to US provisional applications 63/194,847 (filed 28 May 2021) and 63/122,431 (filed 07 December 2020).
This action is responsive to the Response to Restriction Requirement filed 24 March 2026, in which claims 1, 178, 288, and 293 were amended. Claims 1, 4-5, 11-15, 30-33, 159, 163, 288, and 293 are under consideration herein (with claims 16, 22, 37, 40, 178, 298, and 349 being withdrawn; see also paragraphs 5-7 below).
Entry of Non-Compliant Amendment
It is noted that the Amendment filed 24 March 2026 fails to comply with all requirements of 37 CFR 1.121(c), as each claim has not been provided with the correct sequence identifier; specifically, withdrawn claims should be indicated as “Withdrawn” (or if amended as “Withdrawn – currently amended”). While the Amendment has been entered as a courtesy, future amendments should comply with all requirements of 37 CFR 1.121.
Election/Restriction
Applicant’s election without traverse of Group I in the reply filed on 24 March 2026 is acknowledged. Applicant identifies claims 1, 4-5, 11-15, 30-33, 159, 163, 178, 288, and 293 as reading on the elected Group; however, claim 178 as amended 24 March 2026 now corresponds to Group IV. Accordingly, claims 1, 4-5, 11-15, 30-33, 159, 163, 288, and 293 now correspond to Group I.
Claims 16, 22, 37, 40, 178, 298, and 349 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 24 March 2026.
Applicant’s election of the species of an antibody or antibody fragment, and an anti-PD-1 antibody/antibody fragment and MK-3475 (pembrolizumab) in the reply filed on 24 March 2026 is also acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). It is noted that all Group I claims listed above encompass the elected species (with claim 30-33 also reciting alternative, non-elected species).
Claim Interpretation
With regard to the use in the claims of the language “at least about 10 mutations/megabase (mut/Mb)” (see each of independent claims 1, 288, and 293), it is noted that the specification does not define “at least about”, but does state that (see paragraph 109):
The terms “about” or “approximately” as used herein refer to the usual error range for the respective value readily known to the skilled person in this technical field, for example, an acceptable degree of error or deviation for the quantity measured given the nature or precision of the measurements. Reference to “about” or “approximately” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.
As tumor mutational burden (TMB) is commonly reported in the art to one decimal place (e.g., 9.1 mut/Mb, 10.2 mut/Mb) – see, e.g., Chalmers et al (US 2018/0363066 A1 [20 Dec 2018]; cited in IDS) in Table 7, and Klempner et al (The Oncologist 25:e149 [2020]; cited in IDS) at page e155, right column) – the language “at least about 10” mut/Mb has simply been interpreted as requiring a minimum value closer to 10 than 9, e.g., while 9.6 mut/Mb would be considered as meeting the requirement “at least about 10”, 9.4 mut/Mb would not (as a person of skill in the art would consider the latter to be “about 9” rather than “about 10”).
With regard to the recitation of the elected species “MK-3475 (pembrolizumab)” in claim 33, it is noted that the use of parentheses in this case does not render the claims indefinite, as the claim simply recites two alternative known names for the same monoclonal antibody.
Comment Regarding Statutory Subject Matter (35 USC 101)
With regard to independent claims 288 and 293, which are directed to a system and non-transitory computer readable medium, respectively, it is noted that while the claims do set forth activities that may be considered abstract ideas in some contexts – “analyzing” and “detecting” – the claims (while indefinite) specifically require “analyzing” a plurality of sequence reads (obtained from nucleic acids of a sample) for a tumor mutational burden (TMB) of at least 10 mut/MB, and “detecting” such a TMB in the sample. Thus, given the nature of the claimed subject matter, which requires obtaining a plurality of sequence reads derived from a sample and analysis of that data in a manner sufficient to detect presence of the required TMB, the abstract ideas of the claims are of a type that “cannot practically be performed in the human mind” (given the extensive analysis of sequencing data, nature of the alignments/comparisons/etc. required by the claims) (see MPEP 2106.04(a)(2)(III)).
Claim Rejections - 35 USC § 112(b)/second paragraph
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 288 and 293 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.
Claims 288 and 293 are indefinite over the recitation of the language “analyze the plurality of sequence reads for the presence of a tumor mutational burden (TMB)…in an invasive lobular carcinoma (ILC) metastasis of the individual” (claim 288) and “analyzing….the plurality of sequence reads for the presence of a tumor mutation burden (TMB)…in an invasive lobular carcinoma (ILC) metastasis of the individual” (claim 293), because it is unclear how the limitation “in an invasive lobular carcinoma (ILC) metastasis of the individual” relates to and further limits what is claimed. The claims initially recite obtain/obtaining “a plurality of sequence reads of one or more nucleic acids, wherein the one or more nucleic acids from a sample obtained from an individual”, such that the program/instructions involve “an individual” (as opposed to, e.g., an individual known to have an ILC metastasis). While the subsequent recitation “in an invasive lobular carcinoma (ILC) metastasis of the individual” would suggest to some persons of skill in the art that the “obtain”/”obtaining” is to be performed with regard to this more particular type of individual (in order to allow for the practice of the “analyzing” as presently recited in the claims), other such practitioners might interpret the language as requiring some type of (unrecited) further steps/activities that achieve the objective of allowing for the “analyzing” as set forth in the claims. As it is thus unclear what is encompassed and required by the “analyze”/”analyzing” of the claims, such that there are multiple reasonable interpretations of the claims involving different boundaries, further clarification is required.
Claim Rejections - 35 USC § 112(a)/first paragraph – new matter
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 288 and 293 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. This is a new matter rejection.
It is reiterated that claims 288 and 293 are indefinite for the reasons given above; this rejection applies to a possible embodiment that appears to be encompassed by the claims.
Applicant’s amendment of 24 March 2026 added the limitation “in an invasive lobular carcinoma (ILC) metastasis of the individual” to each of claims 288 and 293. Applicant’s disclosure clearly provides basis for programs comprising instructions to obtain sequence reads of nucleic acids “derived from a sample” and analyzing those sequencing reads (see, e.g., original claims 288 and 293), and further discloses such methods in which “the sample is a sample from an individual having an invasive lobular carcinoma (ILC) metastasis” (see, e.g., paragraph 51 of the specification), which requires methods in which the obtain/obtaining is performed with respect to nucleic acids from such a sample, followed by analysis of those nucleic acids. However, the present claims as amended appear to also embrace obtaining sequencing reads from nucleic acids of an individual not known to have an ILC, and subsequently performing analysis of those sequence reads in such a way that analyzing of tumor mutation burden in an ILC is achieved. As such a method was not originally disclosed, Applicant’s amendments to claims 288 and 293 add new matter to the claims.
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, 4-5, 11-15, 30-32, 288 and 293 are rejected under 35 U.S.C. 103 as being unpatentable over Chalmers (US 2018/0363066 A1 [20 Dec 2018]; cited in IDS).
Chalmers et al discloses methods of evaluating/profiling tumor mutational burden (TMB) in a sample (such as a tumor sample or “sample acquired from a tumor”), which methods include “simultaneous detection of actionable alterations for targeted therapies, as well as mutational burden for immune therapies”, and providing “clinically actionable predictors of a response to therapies in patients with cancer” (see entire reference, particularly the Summary at paragraphs 5-9). With more particular regard to the methods steps of independent claim 1:
Chalmers et al teach a variety of possible source sample types for use in their methods, include samples of metastatic lesions (see, e.g., paragraphs 82-85, particularly paragraphs 83-84, as well as paragraph 382 and 393), and teach testing of such samples that results in “acquiring knowledge” of TMB, including using the value of mutations/alterations per megabase Mb (see, e.g., paragraphs 18-21 and 24-32, and the Examples); and
Chalmers et al disclose that a preferred application of their method is “selecting a treatment responsive to the evaluation of mutation load, e.g., an increased level of the mutation load”, and “administering a treatment responsive to the evaluation of mutation load, e.g., an increased level of the mutation load” (see, e.g., paragraph 90).
Among the disclosed values employed by Chalmers et al in their data analysis is a TMB of 10 mutations/Mb (i.e., the value specified in (a) of claim 1)(see paragraph 763 of Chalmers et al, as well as Table 13). Additionally, cancers analyzed by Chalmers et al include invasive lobular carcinoma (ILC) – see the disclosure of 5.4% of breast ILCs tested exhibiting greater than 20 mut/Mb (Table 6 at page 50 of the publication), Table 12, and the 14% and 7% of breast ILCs reported as exhibiting 10 or more mut/Mb and 20 or more mut/Mb, respectively (Table 13 at page 55 of the publication); it is also noted that Chalmers et al state that the “majority of specimens” analyzed with respect to TMB “where from patients with significantly pre-treated, advanced and metastatic disease” (paragraph 778). Further, the stated purpose of the testing reporting in Example 5 (which includes the disclosures of Tables 12-13) is the study of ‘the association of tumor mutation load with predicted benefit from immune checkpoint inhibitors” (see paragraph 808/the first paragraph of Example 5), and the data reported in Table 6 is followed by the statements (see paragraph 780, page 51 of the publication) “Disease indications currently approved for immunotherapies…had high TMB (see Table 6, and note that the values reported as ‘high” in paragraph 780 are a median of 7.2 mut/Mb and 13.5 mut/Mb)), “Identifying additional cancer types with high TMB may represent an opportunity to expand the list of indications that respond favorably to checkpoint inhibitor blockade”, and that their findings support the possibility that “patients with high TMB who may benefit from immunotherapy can be identified in nearly every type of cancer”.
In view of Chalmers 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 – upon acquiring knowledge of a TMB of “at least about 10 mutations/megabase (mut/Mb)” in a sample from an individual with an ILC metastasis – administered to that individual an effective amount of an immune checkpoint inhibitor, thereby treating the subject for the ILC metastasis, and performing a method meeting all requirements of independent claim 1. While Chalmers et al do not exemplify such a method specifically, as outlined above Chalmers et al teach testing for TMB, particularly with regard to breast ILC – disclosing that their testing focused on advanced/pre-treated/metastatic samples, and reporting high TMB (including 10 or more and 20 or more mut/Mb) in many such samples – and further teach that a primary application of such testing is identification of subjects exhibiting high TMB for targeted treatment with immune checkpoint inhibitors. Thus, an ordinary artisan would have recognized such a method as the implementation of what is taught and suggested by Chalmers et al, and would also have been motivated to have performed such a methods for the benefit of more appropriately treating a patient exhibiting high TMB, in the manner taught by Chalmers et al; furthermore, an ordinary artisan would have been motivated to have employed an amount of a particular therapy known to be therapeutically effective, i.e., an “effective amount”, again simply for the benefit of most appropriately/effectively treating a patient. With further regard to dependent claims 4-5, it is reiterated that Chalmers et al teach (human) breast ILC, as discussed above. Regarding claims 11-14, Chalmers et al teach samples comprising fluids, cells, tissues, tumors, circulating tumor cells, and DNA obtained therefrom, etc. (see again, e.g., paragraphs 82-85). Regarding dependent claim 15, Chalmers et al teach preferred embodiments of whole genome and whole exome sequencing (see, e.g., paragraphs 5, 347, 407-408). Regarding claims 30-32, Chalmers et al disclose preferred immunotherapies including PD-1 and PD-L1 inhibitors (see, e.g., paragraphs 781-782), thereby suggesting use of either of these alternatives.
With regard to Applicant’s independent claims directed to a system (claim 288) comprising a memory and one or more processors configured to execute one or more program instructions, and to a non-transitory computer readable storage medium (claim 293) comprising one or more executable programs for performing a method of the same type specified in the system claim, Chalmers et al also teach systems “for evaluating the mutation load in a sample (e.g., a tumor sample or a sample derived from a tumor”, such systems including at least one processor “operatively connected to a memory” and configured to acquire nucleotide sequence of the sample and analyze that sequence to determine/detect a value for mutational load (which has been disclosed by Chalmers et al as encompassing a preferred embodiment of TMB, including a TMB of 10 mut/Mb, as discussed above); see, e.g., paragraphs 86-89 regarding systems, and paragraph 90 regarding the reporting of mutational load, including via delivery of reports that may be electronic or web-based, etc. It is also noted that Chalmers et al disclose preferred methods for mutation calling that require examining sequence reads (see, e.g., paragraphs 574-595), and also disclose employing public databases of SNP/variant information as well as building and employing databases of sequence and mutation data (see, e.g., paragraphs 48, 323, 583, 596, and 636-643), making clear that the analysis employs processors executing program instructions for sequence analysis, mutation analysis, TMB calculations, etc. In view of Chalmers 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 prepared (and employed in the methods suggested by Chalmers et al) a system and non-transitory computer readable media as set forth in claim 288 and 293. An ordinary artisan would have been motivated to have made such a modification by Chalmers et al’s teachings of the benefits of their methods as set forth above, so as to have prepared for use in those methods systems and media usable therein (again, as is explicitly suggested by the teachings of Chalmers et al, given that sequence read analysis, TMB calculations, etc., are disclosed as being carried out via such systems).
Claim(s) 33 is rejected under 35 U.S.C. 103 as being unpatentable over Chalmers et al as applied to claims 1, 4-5, 11-15, 30-32, 288 and 293, above, and further in view of Samstein et al (Nature Genetics 51:202-206 [Feb 2019]; cited herein).
The relevant teachings of Chalmers et al are set forth above, and it is reiterated that (as discussed with respect to dependent claims 31-32, from which claim 33 depends), Chalmers et al disclose preferred immunotherapies including PD-1 and PD-L1 inhibitors (see, e.g., paragraphs 781-782). However, Chalmers et al do not disclose the particular anti-PD-1 antibody pembrolizumab, and thus do not teach all limitations required by claim 33.
Samstein et al teach that that tumor mutational load “predicts survival after immunotherapy across multiple cancer types” (title), stating in particular that high/higher TMB “is associated with improved survival in patients receiving ICI [immune checkpoint inhibitors] across a wide variety of cancer types” (Abstract, and see the entire reference); it is noted that these teachings of Samstein et al are consistent with the teachings of Chalmers et al set forth above regarding high TMB serving as an indicator for ICI responsiveness. Samstein et al disclose that ICI therapy encompasses use of pembrolizumab (see, e.g., page 203, top of left column), and Samstein et al teach that patients “with hypermutated tumors as a result of defective mismatch repair have high response rates to pembrolizumab”, a finding which as “led to the FDA’s tissue/site-agnostic approval” of pembrolizumab for such tumors (page 205, top of left column); Samstein et al also teach that their data “demonstrates the continuous association between higher TMB and superior overall survival” in patients treated with anti-PD-1 therapies (which include pembrolizumab)(page 205, left column). While Samstein et al teach that relevant TMB cutoffs appear to vary by cancer, it is reiterated that Chalmers et al teach thresholds of 10 mut/Mb and 20 mut/Mb (both of which meet the requirements of claim 1) in the context of breast ILC. Thus, in view of the teachings of Samstein 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 of Chalmers et al so as to have administered an effective amount of pembrolizumab to breast ILC patients meeting the TMB threshold of the claims, such that Chalmers et al in view of Samstein et al suggest methods as set forth in claim 33 with respect to the elected species of pembrolizumab. An ordinary artisan would have been motivated to have made such a modification by Samstein et al’s teachings that pembrolizumab has received tissue/site-agnostic FDA approval for use in treating hypermutated tumors, particularly given Samstein et al’s disclosure of the use of high/higher TMB as an factor in making such treatment decisions. Further, given the combined teachings of Chalmers et al and Samstein et al (particularly with regard to the FDA recommended use of pembrolizumab in treating such tumors), an ordinary artisan would have had a reasonable expectation of success in performing such methods.
Claim(s 159 and 163 are rejected under 35 U.S.C. 103 as being unpatentable over Chalmers et al as applied to claims 1, 4-5, 11-15, 30-32, 288 and 293, above, and further in view of Sokol et al (Annals of Oncology 30:115 [online Nov 2018]; cited in IDS).
Again, the teachings of Chalmers et al are set forth above. While Chalmers et al disclose that CDH1 is among a group of genes that may be sequenced/analyzed during the performance of their methods (see Table 1) and is known to exhibit alterations in association with some cancers (see paragraph 434), Chalmers et al do not teach that an ILC metastasis may comprises CDH1 mutations (claim 159), including mutations that may result in loss of function of CDH1 polypeptide (claim 163).
Sokol et al disclose analysis of TMB in ILCs (see entire reference), teaching that elevated TMB suggests possible benefit from ICIs (Abstract), which is consistent with the teachings of Chalmers et al (as set forth above). Sokol et al teach that CDH1 is the most commonly genomically altered gene in metastatic ILCs, reporting that frameshift mutations, nonsense mutations, splicing mutations, missense mutations, and homozygous deletions were all observed (page 116, in particular right column second full paragraph); Sokol et al thus teach detection in ILC metastasis of CDH1 mutations including mutations resulting in loss of function of CDH1 polypeptide (meeting the requirements of both claim 159 and claim 163). It is further noted that CDH1 alterations were so common in ILCs that Sokol et al report using such alterations “as a proxy to identify ILC cases” (page 117, right column bridging to page119, left column, and see also Figure 2).
In view of the teachings of Sokol 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 of Chalmers et al so as to have performed such methods on ILC samples exhibiting CDH1 variations as set forth in claims 159 and 163, and further to have included steps of detecting such variations (although such steps are not necessarily required by the current claim language). First, as Sokol et al teach that such alterations were found to be present in more than 3 of 4 tested ILCs, and may function as a proxy for ILC detection, an ordinary artisan would have been motivated to have included such testing for this benefit (so as to, e.g., simply the process of sample identification and characterization). Second, given the wide variety of CDH1 variations reported by Sokol et al in such samples, an ordinary artisan would have been motivated to have employed methods capable of detecting any such alterations – including any resulting in loss of CDH1 polypeptide – in order to perform such identification and characterization in a manner likely to detect all possible such alterations. Further, given Sokol et al’s teachings regarding the frequency of CDH1 alterations, an ordinary artisan would have had a reasonable expectation of success in performing such methods.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Klempner et al (The Oncologist 25:e149 [2020]; cited in IDS) teach that TMB “is a newly established independent predictor” of ICI treatment outcome “across multiple tumor types”, and provide an overview of its use in various clinical trials (including some involving pembrolizumab)(see entire reference). Sokol et al-2 (Cancer Research 79(13_Supplement): 4894 [2019]; cited in IDS) disclose the study of TMB and PD-L1 expression in breast cancers including ILC, and report employing a TMB cutoff of >10 mut/Mb for “high TMB” (see entire Abstract). Trivedi et al (Acta Medica Academica 48(1):105-115 [2019]; cited herein) describe cases presented to a “Molecular Tumor Board” (MTB), including a case of breast ILC, and multiple (different) cases involving use of pembrolizumab as a “matched targeted therapy” (see entire reference, including Table 2). Le et al (NEJM 372(26):2509 [online May 2015]; cited herein) describe a phase 2 study of pembrolizumab comparing mismatch repair deficient and non-deficient metastatic carcinomas (see entire reference).
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/DIANA B JOHANNSEN/Primary Examiner, Art Unit 1682
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