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 1-20 are pending and currently under examination.
Priority
This application 18/280,513 filed on 09/06/2023 is a 371 national phase of PCT/US2022/019704 filed on 03/10/2022, and claims the benefit of provisional U.S. Patent Application No. 63/159,064, filed on 03/10/2021.
The priority date of independent claim 1 and its dependent claims, 2-11, is determined to be 03/10/2021, the filing date of provisional U.S. Patent Application No. 63/159,064.
The priority date of claim 12 and its dependent claims, 13-20, is determined to be 03/10/2022, the filing date of Application No. PCT/US2022/019704 because provisional U.S. Patent Application No. 63/159,064 is not directed to a method of diagnosing cancer.
Specification
The use of terms which are trade names or marks used in commerce (including Alexa-Fluor® and AmershamTM 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 Objections
Claim 12 is objected to because of the following informalities: Claim 12 includes two steps (f), one before step (g) and one following step(g). Appropriate correction is required. For purposes of examination the second step (f) will be referred to as step (f)[ (step 2)].
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.
Claims 5 and 12-20 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 5 recites the limitation "the epigenetic modification" in line 1. There is insufficient antecedent basis for this limitation in the claim. It is assumed the claim is intended to read “the at least one epigenetic modification” as in claim 2.
Claim 12 recites the limitations “(g) quantifying a number of epigenetic modifications in the target DNA strand; (f) [step 2] comparing the number of epigenetic modifications to a reference epigenetic profile for cancer; and (h) diagnosing the subject as having cancer when the quantifying of step (g) correlates with the reference epigenetic profile for cancer.” It is unclear how one is intended to diagnose the subject. It is unclear what elements, if any, are required for comparison from the reference epigenetic profile. It is unclear if the identity or location of the epigenetic modifications are important, or, as written, simply the number of epigenetic modifications. It is unclear what would constitute a correlation with the reference epigenetic profile.
Claims 13-20 are similarly indefinite because they directly or indirectly depend from claim 12.
Claim 14 recites the limitation "the epigenetic modification" in line 1. There is insufficient antecedent basis for this limitation in the claim. It is assumed the claim is intended to read “the at least one epigenetic modification” as in claim 12.
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 10 and 12-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106, part II.
Based upon consideration of the claims as a whole, as well as consideration of elements/steps recited in addition to the judicial exception, the present claims fail to meet the elements required for patent eligibility.
Step 1
The claimed invention is directed to the statutory category of a process.
Step 2A, Prong One
The claims are taken to be directed to abstract ideas and a law of nature, judicial exceptions.
Claim 10 is directed to a method comprising “quantifying a number of epigenetic modifications of the target DNA strand”. This limitation is an abstract mental process that broadly encompasses mathematical concepts such as mathematical calculations (see MPEP 2106.04(a)(2)(I)). As written, the quantifying step encompasses the mental step of counting the number of epigenetic modifications.
Claim 12 is directed to a method comprising “(g) quantifying a number of epigenetic modifications of the target DNA strand”. This limitation broadly encompasses mathematical concepts such as mathematical calculations (see MPEP 2106.04(a)(2)(I)). As written, the quantifying step encompasses the mental step of counting the number of epigenetic modifications.
Claim 12 is directed to a method comprising “(f) comparing the number of epigenetic modifications to a reference epigenetic profile”. This limitation is an abstract mental process (see MPEP 2106.04(a)(2)(III)). As written, the comparing step encompasses the mental step of looking at epigenetic profiles and making mental judgements.
Claim 12 is directed to a method comprising “(h) diagnosing the subject as having cancer when the quantifying of step (g) correlates with the reference epigenetic profile for cancer”. This diagnosing element of the limitation is an abstract mental process (see MPEP 2106.04(a)(2)(III)). As written, the diagnosing step encompasses the mental step of looking at epigenetic profiles and making mental judgements.
This element further recites the judicial exception of a law of nature. The claim recites a correlation between having cancer and an alteration in an epigenetic profile. As written, this limitation encompasses a condition that preexists in a subject and is an unpatentable phenomenon.
Claims 13-20 depend from claim 12 , and require the same steps of quantifying, comparing and diagnosing steps in independent claim 12.
Step 2A, Prong Two
The exception is not integrated into a practical application of the exception. The claims do not recite any additional elements that integrate the exception into a practical application of the exception.
While claims 1 and 12 recite ”providing a target DNA strand comprising at least one epigenetic modification; annealing a single-stranded DNA probe to the target DNA strand-- ; immobilizing the annealed DNA on a support; contacting the immobilized DNA with a primary antibody --; contacting the immobilized DNA with a secondary antibody --; and detecting the fluorophore using prism-based single molecule total internal reflection fluorescence (TIRF) microscopy”, these are not integrations of the exception into a practical application. Instead, these elements are data gathering required to perform the method.
Step 2B
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception. The claim does not add a specific limitation other than what is well-understood, routine, and conventional in the field. Steps directed to annealing probes, immobilizing annealed NDA, contacting immobilized DNA with primary and secondary antibodies and performing TIRF are techniques that are mere data gathering steps that are routine, conventional, and well-known in the art as demonstrated in the 103 rejections documented below.
Furthermore, the courts have recognized the following laboratory techniques as well-understood, routine, conventional activities in the life science arts when they are claimed in a merely generic manner or as insignificant extra-solution activity:
i. Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
ii. Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
iii. Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247.
For these reasons, the claims are rejected under section 101 as being directed to non-statutory subject matter.
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 1-11 are rejected under 35 U.S.C. 103 as being unpatentable over Collins et al. (US 20180023124).
Regarding claim 1, Collins teaches methods of detecting a genetic variation in a genetic sample, the method comprising: contacting probes with target molecules to form probe-target molecule complexes (i.e. by annealing) (para 29). Collins teaches that methylated regions of the genome (DNA with epigenetic modifications) can be identified using antibodies specific for 5-methylcytosine (para 505), which reads on “a primary antibody” recited in step (d) of claim 1. Collins teaches that probes can be single-stranded (para 99) and labeled with biotin (para 240) and immobilized to a solid support by means of avidin, streptavidin or neutravidin (para 26). Regarding limitations of steps (d) and (e), Collins teaches using antibodies specific for 5-methylcytosine (para 505) and the use of secondary antibodies carrying a label (para 401), which reads on “a secondary antibody” recited in step (e) of claim 1. Collins also teaches the use of prism-based TIRF microscopy to detect fluorophores (para 57, Figs. 76 and 77 and para 830).
Collins does not teach verbatim “contacting the immobilized DNA with a primary antibody that binds to at least one epigenetic modification” recited in step (d) of claim 1 or “contacting the immobilized DNA with a secondary antibody labeled with a fluorophore that binds to the primary antibody” recited in step (e) of claim 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 modify the teachings of Collins to arrive at the instantly claimed invention. The modification would have entailed selecting epigenetic modifications as the genetic variant of interest and directly detecting epigenetic modifications by using antibodies with fluorophore labels to provide the fluorescent single-molecule signal measured by Collin with TIRF. Collins taught that methylated regions can be identified by antibody (para 505). Secondary antibodies are commonly labeled with a fluorophore and one of ordinary skill in the art would have known to use a secondary antibody that binds to a primary antibody. One would have been motivated by the flexibility and signal amplification provided by the use of primary and secondary antibodies instead of direct labeling, advantages that were well-known and standard in the art before the effective filing date of the claimed invention. 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 claim 2, Collins teaches a target can be DNA (i.e. double stranded), and that a nucleic acid strand of interest (target DNA strand) can be a single stranded nucleotide molecules from double stranded nucleotide molecules (i.e. target and non-target strands) of the genetic sample (para 162). Collins also teaches samples comprising a sense (target) strand annealed to a non-target (anti-sense) strand) (Fig. 62).
Regarding claim 3, Collins teaches samples may be denatured before an assay is performed (para 85), and hybridizing a probe to a sense nucleic acid strand of interest (target strand) in single stranded nucleotide molecules from double stranded nucleotide molecules (i.e. target and non-target strands) of the genetic sample (para 162), which satisfies the requirement of denaturing the target and non-target strands.
Regarding claim 4, Collins teaches the epigenetic modification 5-methylcytosine (para 505).
Regarding claim 5, Collins teaches detecting genetic variants that indicate presence of cancer (para 803).
Regarding claim 6, Collin teaches immobilized to a solid support by means of avidin, streptavidin or neutravidin (para 26).
Regarding claim 7, Collin teaches immobilization by biotin-oligonucleotides complexed with avidin (para 26).
Regarding claim 8, Collin teaches the solid substrate comprises quartz (para 230).
Regarding claim 9, Collins teaches the sample can include cell-free DNA (para 77).
Regarding claim 10, Collins teaches quantifying genetic variants (para 76).
Regarding claim 11, Collins teaches fluorophore labels including Cy3 and Cy5 (para 131).
Claims 12-20 are rejected under 35 U.S.C. 103 as being unpatentable over Collins et al. (US 20180023124) in view of Song et al. (US 20170298422 on IDS dated 01/30/2024).
Regarding claim 12, Collins teaches methods of detecting a genetic variation in a genetic sample that can be from a patient source (para 77) and directed to determining risk of disease such as cancer on the basis of the variation (para 74), the method comprising: contacting probes with target molecules to form probe-target molecule complexes (i.e. by annealing) (para 29). Collins teaches that methylated regions of the genome (DNA with epigenetic modifications) can be identified using antibodies specific for 5-methylcytosine (para 505). Collins teaches that probes can be single-stranded (para 99) and labeled with biotin (para 240) and immobilized to a solid support by means of avidin, streptavidin or neutravidin (para 26). Regarding limitations of steps (d) and (e), Collins teaches using antibodies specific for 5-methylcytosine (para 505) and the use of secondary antibodies carrying a label (para 401). Collins also teaches the use of prism-based TIRF microscopy to detect fluorophores (para 57, Figs. 76 and 77 and para 830). Collins further teaches quantifying genetic variants (para 76).
Collins does not specifically teach contacting the immobilized DNA with a primary antibody that binds to at least one epigenetic modification or contacting the immobilized DNA with a secondary antibody labeled with a fluorophore that binds to the primary antibody.
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 modify the teachings of Collins to arrive at the instantly claimed invention. The modification would have entailed selecting epigenetic modifications as the genetic variant of interest and directly detecting epigenetic modifications by using antibodies with fluorophore labels to provide the fluorescent single-molecule signal measured by Collin with TIRF. Collins taught that methylated regions can be identified by antibody (para 505). Secondary antibodies are commonly labeled with a fluorophore and one of ordinary skill in the art would have known to use a secondary antibody that binds to a primary antibody. One would have been motivated by the flexibility and signal amplification provided by the use of primary and secondary antibodies instead of direct labeling, advantages that were well-known and standard in the art before the effective filing date of the claimed invention. 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.
Collins does not teach diagnosing cancer by (f) [step 2] comparing the number of epigenetic modifications to a reference epigenetic profile for cancer; and (h) diagnosing the subject as having cancer when the quantifying of step (g) correlates with the reference epigenetic profile for cancer.
Song teaches a method for analyzing genomic DNA and detecting and quantifying epigenetic modifications (5mC and 5hmC) (para 5) and providing diagnosis based on the results of the method (para 67). The method comprises providing a sample from a subject of interest (para 64), the sample comprising a target DNA strand with at least one epigenetic modification, and quantifying the epigenetic modifications using TIRF (para 7).
Song further teaches using the above method to identify an epigenetic signature for a patient (e.g. subject suspected of having cancer); comparing the patient signature to a set of signatures correlated with a disease (e.g. reference epigenetic profile for cancer); and making a diagnosis based on the correlation with the phenotype (para 68). The phenotype may include the presence or likelihood of cancer (para 79).
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 Collins and Song to arrive at the instantly claimed invention. The modification would have entailed applying the method of Collins to a patient as taught in Collins and analyzing the data as taught by Song to choose a treatment for the patient. One would have been motivated by the ability to use the method of Collins to provide medical benefits as described in Song. Both Collins and Song taught the association of genetic variants and modifications with disease and the method of Song provided a tool to apply the method of Collins. 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 claim 13, Collins teaches fluorophore labels including Cy3 and Cy5 (para 131).
Regarding claim 14, Collins teaches the epigenetic modification 5-methylcytosine (para 505).
Regarding claim 15, Collin teaches immobilized to a solid support by means of avidin, streptavidin or neutravidin (para 26).
Regarding claim 16, Collin teaches immobilization by biotin-oligonucleotides complexed with avidin (para 26).
Regarding claim 17, Collin teaches the solid substrate comprises quartz (para 230).
Regarding claim 18, Collins teaches the sample can include cell-free DNA (para 77).
Regarding claim 19, Collins teaches the sample can be from blood, serum, plasma or urine (para 77).
Regarding claim 20, Collins teaches the invention can be used for early detection and pharmaceutical treatment in oncology (para 804) but does not teach treating the diagnosed subject with a therapeutic agent specific for the cancer.
Song teaches using the epigenetic signature to diagnose a disease and indicate a treatment which would be the most effective (para 67), which reads on treating the diagnosed subject with a therapeutic agent specific for the cancer.
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 Collins and Song to arrive at the instantly claimed invention. The modification would have entailed applying the method of Collins to a patient as taught in Collins and analyzing the data as taught by Song to choose a treatment for the patient. One would have been motivated by the ability to use the method of Collins to provide medical benefits as described in Song. Both Collins and Song taught the association of genetic variants and modifications with disease and the method of Song provided a tool to apply the method of Collins. 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 1-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1,2, 5, 8-12, 14, 15, and 31-33 of copending Application No. 17/283,378 (reference application) in view of Collins et al. (US 20180023124).
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. Each claim set is drawn to a method of quantifying epigenetic modifications in DNA using probes labeled with that anneal to target DNA, are immobilized to a support with avidin, using TIRF to detect fluorophores on a quartz surface.
The additional limitations of the ‘378 claims are encompassed by the open claim language "comprising" found in the instant claims.
The claims of ‘378 do not teach the use of antibodies to epigenetic modifications.
The teachings of Collins as they relate to these claims are given previously in this office action and are fully incorporated here.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(II). Claims 12-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1,2, 5, 8-12, 14, 15, and 31-33 of copending Application No. 17/283,378 (reference application) in view of Song et al. (US 20170298422 on IDS dated 01/30/2024).
The claims of ‘378 do not teach diagnosing cancer in a subject or treating a diagnosed subject.
The teachings of Song as they relate to these claims are given previously in this office action and are fully incorporated here.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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/JESSICA GRAY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682