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 .
Claims 21-40 are pending and currently under examination.
Priority
This application 18/768,466 filed on 07/10/2024 is a continuation of 17/166,394 filed 02/03/2021 (now US Patent No. 12,065,691), which is a continuation of 16/053,610 filed 08/02/2018 (now US Patent No. 10,947,579), which is a continuation of Internation Patent Application PCT/US17/32466 filed 05/12/2017, which claims the benefit of provisional U.S. Patent Application No. 62/410,599 filed 10/20/2016 and claims the benefit of provisional U.S. Patent Application No. 62/336,252 filed 05/13/2016.
The priority date of claim 21 and its dependent claims is determined to be 05/13/2016, the filing date of provisional U.S. Patent Application No. 62/336,252.
Specification
The use of terms which are trade names or marks used in commerce (including IIlumina® and MiSeqTM among others), has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM, or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112(b)
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.
Claim 38 is 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 38 recites the limitation “wherein said reference genome is a wild type genome of a species common to the subject”. It is unclear what criteria would identify a reference genome as “common to the subject”. The phrase “common to the subject” encompasses both a wildtype genome of an individual for comparing to protein-DNA complexes isolated from a tumor of the same individual as well as a wildtype genome from another subject from the same species.
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.
Claims 21,23-35, and 39-40 are rejected under 35 U.S.C. 103 as being unpatentable over Lieberman-Aiden et al. (Comprehensive Mapping of Long-Range Interactions Reveals Folding Principles of the Human Genome", Science, October 2009, 326(5950):289-293. On IDS dated 02/25/2025) in view of Cejas et al. (Chromatin immunoprecipitation from fixed clinical tissues reveals tumor-specific enhancer profiles. 2016. Nat Med 22: p. 1-8, published online 04/25/2016).
Regarding claim 21, Lieberman-Aiden teaches a method for mapping long-range interactions (Hi-C), the method comprising obtaining a formaldehyde fixed sample (p. 1, col. 2) wherein chromatin (protein-DNA complexes) are preserved (Fig. 1A). Lieberman-Aiden teaches chromatin (protein-DNA complexes) comprising a first double-stranded segment and a second double-stranded segment; digesting the chromatin with a restriction enzyme (nuclease) such that the first double-stranded segment and said second double-stranded segment each have at least one exposed nucleic acid end; ligating the exposed nucleic acid ends of the first and second double-stranded segment( Fig. 1A). Lieberman-Aiden further teaches determining intrachro-mosomal interactions by analyzing the nucleic acids from the chromatin (protein-DNA complexes) in the fixed sample (Figs. 1A and 1B).
Lieberman-Aiden does not teach (1) the formaldehyde crosslinked sample is a formalin fixed paraffin-embedded (FFPE) from a subject or (2) treating said protein-DNA complexes of said FFPE sample with a proteinase to generate a plurality of treated protein-DNA complexes.
Cejas teaches chromatin immunoprecipitation from fixed clinical tissues, the method comprising obtaining FFPE samples from a subject and treating samples with proteinase K and isolating chromatin (protein-DNA complexes) (p. 8, col. 1), thus satisfying the requirement of treating said protein-DNA complexes of said FFPE sample with a proteinase to generate a plurality of treated protein-DNA complexes. Cejas states that FFPE tissue samples represent an enormous source of material for informative epigenome analyses (p. 1, col. 1)
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Lieberman-Aiden and Cejas to arrive at the instantly claimed invention. The modification would have entailed using the FFPE fixed specimens of Cejas as the starting sample of Lieberman-Aiden and further following the protocol of Cejas (including proteinase treatment) to successfully isolate chromatin from the FFPE. One would have been motivated by the ability to use clinical samples as a source for the chromatin in the method of Lieberman-Aiden in order to apply the method of Lieberman-Aiden teaches to medical conditions. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claims 23-26, Cejas teaches performing a micrococcal nuclease (MNase) digestion as a nuclease treatment (p. 8, col. 1). MNase has both endonuclease and exonuclease activity, thus satisfying the requirements of claims 23-26.
Regarding claims 27 and 29, Cejas teaches the use of FFPE samples with formalin cross-linking (p. 1 col. 1).
Regarding claim 28, Cejas teaches crosslinking of FFPE samples with formalin but does not teach crosslinking with formaldehyde. However, Cejas teaches cross-linking fresh frozen tissues with formaldehyde to examine the effects of fixation (p. 2, col. 1).
Thus, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Lieberman-Aiden and Cejas to arrive at the instantly claimed invention. The modification would have entailed substituting the formaldehyde crosslinking as tested by Cejas as the fixative for the FFPE samples. The substitution of one well-known reagent with known properties for a second well known reagent with well-known properties would have been prima facie obvious to the ordinary artisan at the time of the invention in the absence of an unexpected result. Furthermore, determining the appropriate fixative is deemed merely a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claims 30 and 31, neither Lieberman-Aiden nor Cejas teach verbatim the FFPE sample is stored for at least one week prior to (a) (claim 30) or the FFPE sample is stored for at least six months prior to (a) (claim 31).
However, Cejas teaches archive duration was not a limiting factor; samples stored for 10 years gave signals comparable to those of more recently preserved specimens (p. 7, col. 1), which reads on an FFPE sample stored for at least one week or at least six months prior to obtaining the FFPE sample.
Regarding claim 32, Cejas teaches the use of an FFPE sample that is not homogenized (p. 8, col. 1).
Regarding claims 33-35, Cejas teaches washing the FFPE tissue sections with xylene and ethanol (p. 8, col. 1).
Regarding claim 39, Cejas teaches FFPE sections from tumor specimens (p. 8, col. 1), which reads on tissue slices.
Regarding claim 40, Lieberman-Aiden teaches chromatin (protein-DNA complexes) comprising a first double-stranded segment and a second double-stranded segment (Fig. 1A).
Claims 22 and 37-38 are rejected under 35 U.S.C. 103 as being unpatentable over Lieberman-Aiden et al. (Comprehensive Mapping of Long-Range Interactions Reveals Folding Principles of the Human Genome", Science, October 2009, 326(5950):289-293. On IDS dated 02/25/2025) in view of Cejas et al. (Chromatin immunoprecipitation from fixed clinical tissues reveals tumor-specific enhancer profiles. 2016. Nat Med 22: p. 1-8, published online 04/25/2016) as applied to claims 21,23-35, and 39-40 above, and further in view of Dekker et al. (US 20130096009. On IDS dated 02/25/2025).
Regarding claim 22, neither Lieberman-Aiden nor Cejas teach (d) comprises binding a punctuation oligonucleotide to said exposed nucleic acid end of said first double-stranded segment and said exposed nucleic acid end of said second double-stranded segment.
Dekker teaches Hi-C methods and protocols.
Dekker teaches ligating a junction marker (punctuation oligonucleotide) to the ends of the first and second stranded segments (Fig. 4, top figure “non-sticky overhangs”. Dekker teaches a junction marker can provide selective purification, or act as a label or primer linker (para 14).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Lieberman-Aiden and Cejas to arrive at the instantly claimed invention. The modification would have entailed ligating the nucleic acid ends of the two strands using an intermediary nucleotide linker. One would have been motivated to use a linker for the benefits stated by Dekker, namely the ability to selectively purify or label the ligated product for downstream analysis. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claims 37 and 38, neither Lieberman-Aiden nor Cejas teach the structural variant is one of the recited variants of claim 37.
Dekker teaches the method can identify translocations, deletions, insertions, inversions (para 263). Dekker states these variants may provide a genetic basis for human diseases (para 263). Dekker further teaches aligning the data from a Hi-C library to a human reference genome sequence (para 192), which reads on a reference sequence common to the subject, i.e. from the same species.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Lieberman-Aiden and Cejas to arrive at the instantly claimed invention. The modification would have entailed analyzing the date from the Hi-C method of Lieberman-Aiden as taught by Dekker. One would have been motivated to add the analysis of Dekker to expand the method of Lieberman-Aiden to include insight into genetic diseases.
There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Claim 36 is rejected under 35 U.S.C. 103 as being unpatentable over Lieberman-Aiden et al. (Comprehensive Mapping of Long-Range Interactions Reveals Folding Principles of the Human Genome", Science, October 2009, 326(5950):289-293. On IDS dated 02/25/2025) in view of Cejas et al. (Chromatin immunoprecipitation from fixed clinical tissues reveals tumor-specific enhancer profiles. 2016. Nat Med 22: p. 1-8, published online 04/25/2016) as applied to claims 21,23-35, and 39-40 above, and further in view of Kool et al. (WO2016044313, published 03/24/2016)
Regarding claim 36, neither Lieberman-Aiden nor Cejas teach treating said FFPE sample with anthranilate, phosphanilate, or a combination thereof.
Kool is directed to removing aldehyde adducts in FFPE tissue samples.
Kool teaches treating samples with anthranilates and phosphanilates (p. 34, lines 5-7). Kool states that common existing methods for the removal of adducts can cause extensive degradation and loss of nucleic acids, but that treatment with anthranilate and phosphanilate catalysts speed the reversal of formaldehyde adducts of mononucleotides by a substantial factor over standard buffers (p. 34, lines 5-7).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Lieberman-Aiden and Cejas with Kool to arrive at the instantly claimed invention. The modification would have entailed treating the FFPE samples of Cejas with the anthranilates or phosphanilates of Kool for the stated benefit of a speedier (and thus less damaging to nucleic acids) treatment to remove formaldehyde adducts from the FFPE sample. In order to perform the method of Lieberman-Aiden one would be motivated to retain as many undamaged nucleic acids as possible from the starting sample. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
(I). Claims 21, 22, and 27-37 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, 7-11, and 13-15 of U.S. Patent No. 10,947,579.
Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims substantially anticipate the identified claims of this application. The additional limitations of the ‘579 claims are encompassed by the open claim language "comprising" found in the instant claims.
Regarding instant claim 21, claim 1 of the ‘579 patent requires obtaining a preserved sample from a subject, the sample comprising protein-DNA complexes and wherein the preserved sample is a formalin fixed paraffin-embedded (FFPE) sample; treating the preserved sample with a proteinase such that protein-DNA complexes are not destroyed; such that a first double-stranded segment and a second double-stranded segment are held together independent of a phosphodiester backbone, and such that the first double-stranded segment and the second double-stranded segment each have at least one exposed nucleic acid end; and deriving genomic structural information by analyzing nucleic acids of the protein-DNA complexes in the sample. Claims 7 and 9 of the ‘579 patent requires tagging an exposed nucleic acid end of the first double-stranded segment and an exposed nucleic acid end of the second double-stranded segment so as to convey physical linkage information (‘579 claim 7) wherein the tagging comprises ligating an exposed end of the first double-stranded segment to an exposed end of the second double-stranded segment to form a paired end molecule (‘579 claim 9).
Regarding instant claim 22, claim 8 of the ‘579 patent requires wherein the tagging comprises ligating an oligonucleotide to an exposed end of the first double-stranded segment of the preserved sample such that the oligonucleotide conveys information indicative of genomic structural information, which reads on binding a punctuation oligonucleotide to said exposed nucleic acid end of said first double-stranded segment and said exposed nucleic acid end of said second double-stranded segment.
Regarding instant claim 27, claim 2 of the ‘579 patent requires the preserved sample is crosslinked.
Regarding instant claim 28, claim 3 of the ‘579 patent requires the preserved sample is crosslinked using formaldehyde.
Regarding instant claim 29, claim 3 of the ‘579 patent requires the preserved sample is crosslinked using formalin.
Regarding instant claim 30, claim 14 of the ‘579 patent requires wherein the preserved sample is stored for at least one week prior to isolating nucleic acids.
Regarding instant claim 31, claim 15 of the ‘579 patent requires wherein the preserved sample is stored for at least 6 months prior to isolating nucleic acids.
Regarding instant claim 32, claim 13 of the ‘579 patent requires wherein the preserved sample is not homogenized prior to isolating nucleic acids.
Regarding instant claims 33-35, claim 10 of the ‘579 patent requires the preserved sample is treated by contacting the preserved tissue sample to at least one of xylene and ethanol.
Regarding instant claim 36, claim 11 of the ‘579 patent requires wherein the preserved sample is treated by contacting the preserved tissue sample to at least one of an anthranilate and a phosphanilate.
Regarding instant claim 37, claim 5 of the ‘579 patent requires the genomic structural information is indicative of a structural variant comprising at least one of an inversion, an insertion, a deletion, a chromosomal translocation, a copy number variant, a loss of heterozygosity, or a gene fusion relative to a reference genome.
(II). Claims 21, 22, and 27- 37 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, 7-11, and 13-15 of U.S. Patent No. 12,065,691.
Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims substantially anticipate the identified claims of this application. The additional limitations of the ‘691 claims are encompassed by the open claim language "comprising" found in the instant claims.
Regarding instant claim 21, claim 1 of the ‘691 patent requires obtaining a formalin fixed paraffin-embedded (FFPE) sample from a subject, the FFPE sample comprising protein-DNA complexes; treating the FFPE sample with a proteinase to isolate nucleic acids such that the protein-DNA complexes are not destroyed, such that a first double-stranded segment and a second double-stranded segment are held together independent of a phosphodiester backbone, and such that the first double-stranded segment and the second double-stranded segment each have at least one exposed nucleic acid end; and deriving genomic structural information by analyzing nucleic acids of the protein-DNA complexes in the FFPE sample. . Claims 7 and 9 of the ‘691 patent requires tagging an exposed nucleic acid end of the first double-stranded segment and an exposed nucleic acid end of the second double-stranded segment so as to convey physical linkage information (‘691 claim 7) wherein the tagging comprises ligating an exposed end of the first double-stranded segment to an exposed end of the second double-stranded segment to form a paired end molecule (‘691 claim 9).
Regarding instant claim 22, claim 8 of the ‘579 patent requires wherein the tagging comprises ligating an oligonucleotide to an exposed end of the first double-stranded segment of the preserved sample such that the oligonucleotide conveys information indicative of genomic structural information, binding a punctuation oligonucleotide to said exposed nucleic acid end of said first double-stranded segment and said exposed nucleic acid end of said second double-stranded segment.
Regarding instant claim 27, claim 2 of the ‘691 patent requires wherein the FFPE sample is crosslinked.
Regarding instant claim 28, claim 3 of the ‘691 patent requires wherein the FFPE sample is crosslinked using formaldehyde.
Regarding instant claim 29, claim 3 of the ‘691 patent requires wherein the FFPE sample is crosslinked using formalin.
Regarding instant claim 30, claim 14 of the ‘691 patent requires wherein the FFPE sample is stored for at least one week prior to isolating nucleic acids.
Regarding instant claim 31, claim 15 of the ‘691 patent requires wherein the FFPE sample is stored for at least 6 months prior to isolating nucleic acids.
Regarding instant claim 32, claim 13 of the ‘691 patent requires wherein the FFPE sample is not homogenized prior to isolating nucleic acids.
Regarding instant claims 33-35, claim 10 of the ‘691 patent requires wherein the FFPE sample is treated by contacting the FFPE sample to at least one of xylene and ethanol.
Regarding instant claim 36, claim 11 of the ‘691 patent requires wherein the FFPE sample is treated by contacting the FFPE sample to at least one of an anthranilate and a phosphanilate.
Regarding instant claim 37, claim 5 of the ‘691 patent requires wherein the genomic structural information is indicative of a structural variant comprising at least one of an inversion, an insertion, a deletion, a chromosomal translocation, a copy number variant, a loss of heterozygosity, or a gene fusion relative to a reference genome.
Conclusion
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/JESSICA GRAY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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