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 .
The supplemental amended claims dated 6/10/2024 are under consideration.
Priority
The present application is a continuation of PCT/US22/71365 (filed 3/25/2022), which claims benefit of US provisional application 63/166,200 (filed 3/25/2021).
Priority is recognized.
Information Disclosure Statement
The listing of references in the specification or the citation of references throughout the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892 or on a submitted IDS, they have not been considered.
Drawings
High resolution copies of the drawings may be accessed via PAIR/Patent Center Retrieval using the Supplemental Content tab.
Specification
The disclosure is objected to because of the following informalities: the specification recites “MethylMiner®methylated” rather than “MethylMiner® methylated”.
Appropriate correction is required.
The use terms that are trade names or marks used in commerce, such as MethylMiner®, Accel-NGS®, Bavencio®, NovaSEQ™ and MinION™, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore, the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. While some trade names like MethylMiner® and Bavencio® are indicated with a proper symbol, others such as NovaSEQ™ and MinION™ are not.
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 1 is objected to because of the claim includes periods following the item identifiers (i.e. "i.", "ii.", etc.). MPEP 608.019(m) states:
Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v. Manbeck, 36 USPQ2d 1211 (D.D.C. 1995). Where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation, 37 CFR 1.75(i).
Claim Rejections - 35 USC § 112
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 104-123 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.
Regarding claim 104, the claim recites “the at least one epigenetic target region set” in lines 7-8. The recitation lacks proper antecedent basis. Amending the claim to recite “the at least an epigenetic target region set” or amending line 6 to recite “at least one epigenetic target region set of DNA” may address this issue.
Claim 105-118 and 120-123 depend from claim 104 and are rejected for the same reason.
Regarding claim 119, the claim is incomplete as it depends from itself and the recitations “the subsamples” and “the sequencing” lack proper antecedent basis.
Regarding claim 121, the claim states “wherein the levels of each of the plurality of immune cell types are determined relative to levels of total blood cells”. Based on the use of the passive voice it is unclear if applicant intends the claim to require an active method step of “determining the levels of each of the plurality of immune cell types relative to levels of total blood cells”.
Furthermore, the claim is incomplete as there is nothing in the claim determines that “total blood cells” that is required in order to determine the relative levels of cells.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 106 and 119 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 106 recites the elements of step (b) of claim 104, and does not further limit those elements nor does it require any additional elements or steps beyond that claim 104. Claim 106 fails to further limit claim 104.
Claim 119 depends from itself and thus fails to reference “a claim previously set forth”.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claim(s) 104-106, 110-111, 118-119 and 122 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kennedy 1 (WO 2018/119452 A2) in view of Kennedy 2 (US 2018/0305738 A1) and Lai (Genome Res. 2013. 23:2030-2041 and Supplemental Material).
Regarding claims 104, 106, 110-111 and 122, Kennedy 1 teaches providing a population of cell-free DNA from a biological sample and fractionating the population of cell-free DNA based on the methylation level of the cell-free DNA (para. 33) as encompassed by step (a).
Kennedy 1 further teaches nucleic acids in a sample can be subjected to target enrichment, in which molecules having target sequences are captured for subsequent analysis (para. 187), as encompassed by step (b).
Kennedy 1 further teaches amplifying at least one of the subpopulations of cell-free DNA and, sequencing at least one of the amplified subpopulations of cell-free DNA as encompassed by aspects of step (c).
Kennedy 1 further teaches that expansion of cells can be monitored using the methods (para. 195) and adjusting for changes in cell-type composition is carried out when analyzing and interpreting findings from liquid biopsy (para. 216), as encompassed by step (c).
Kennedy 1 further teaches an interest in tracking the amounts of immune cell populations, stating “Immune cells, such as B cells, may undergo rapid clonal expansion upon the presence certain diseases. Clonal expansions may be monitored using copy number variation detection and certain immune states may be monitored. In this example, copy number variation analysis may be performed over time to produce a profile of how a particular disease may be progressing” and “The present methods may be used to determine or profile rejection activities of the host body, as immune cells attempt to destroy transplanted tissue to monitor the status of transplanted tissue as well as altering the course of treatment or prevention of rejection” (para. 195). Kennedy 1 further teaches non-cancer cells includes immune cells such as macrophages, leukocytes and lymphocytes, stromal fibroblasts, myofibroblasts, myoepithelial cells and adjusting for changes in cell-type composition is carried out when analyzing and interpreting findings from liquid biopsy (para. 216). Additionally, Kennedy 1 teaches leukocyte-derived cfDNA changes can also be indicative of immune response to disease (para. 105).
While Kennedy 1 teaches the above methods, Kennedy 1 does not describe “target-specific probes for the at least one epigenetic target region”, or “target regions of the epigenetic target region set comprises DNA sequences that are differentially methylated in a plurality of immune cell types” as described in the claim.
Kennedy 2 teaches that probe panel can comprise a plurality of subpanels, including for capturing differential methylated regions (DMRs)) and for markers of tissue of origin in the form tissue-specific epigenetic markers (para. 169).
Lai demonstrates that DMRs are known that differentiate naïve B cells from activated B cell in the form of germinal center B cells and antibody secreting plasma cells (Table S2).
It would have been prima facie obvious to the ordinary artisan at the time of filing to have modified the method of Kennedy 1 for the detection and quantitation of naïve and activated B cell populations. One would have been motivated to have designed probes that target and capture the known DMRs of Lai in order to track B cells that may be undergone clonal expansion, which is indicative of a disease state. The medication has a reasonable expectation of success as it transforms the generic method of Kennedy 1 and Kennedy 2 into a specific method for the detection of B cell populations.
Regarding claim 105, Kennedy 1 teaches fractionating the population of cell-free DNA based on the methylation level using a methylation binding domain ("MBD") of a methylation binding protein ("MBP") (para. 132).
Regarding claim 118, Kennedy 1 teaches ligating adaptors and amplification of nucleic acids before sequencing (para. 213, 298).
Regarding claim 119, if the claim is amended to depend from claim 104, Kennedy 1 teaches pooling different populations that were separated based on methylation levels (para. 10).
Claim(s) 107-117 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kennedy 1 (WO 2018/119452 A2) in view of Kennedy 2 (US 2018/0305738 A1) and Lai (Genome Res. 2013. 23:2030-2041 and Supplemental Material) as applied to claim 104 above and in further view of Kennedy 3 (WO 2022/073011 A1; priority dates of 10/23/2020 and 9/30/2020).
Regarding claims 107-117, the combination of Kennedy 1, Kennedy 2 and Lai renders obvious the elements of claim 104 as described above and as required by claims 107-117.
Regarding claim 110-112 and 115-117, Lai teaches differential methylation between different states of B cells as described above.
Kennedy 1 further teaches that hypermethylation and hypomethylation separation is based on selecting molecules with particular numbers of methylated nucleotides, e.g., 2, 3, 5, 6, etc. (para. 211).
Thus, the level of methylation differences in claim 111-112 and 116-117 is rendered obvious in view of the references.
The combination does not teach the additional elements specific to claims 107-109 and 113-114.
However, Kennedy 3 teaches methods for improving signal to noise ratio in DNA methylation partitioning assays, such as those of Kennedy 1 and Kennedy 2.
Regarding claims 107-109 and 113-114, Kennedy 3 teaches digesting the nucleic acid molecules in a partitioned set (e.g., a hypomethylated partition) with an enzyme, such as FspEI and digesting the nucleic acid molecules in at least one partitioned set (e.g., a hypermethylated partition) with an enzyme, such as BstUI, Hpall and Hin6I.
The specification identifies FspEI as an “MDRE” in paragraph 207 and identifies at least BstUI as an “MSRE” in paragraph 208.
It would have been prima facie obvious to the ordinary artisan at the time of filing to have further modified the methods of Kennedy 1 and Kennedy 2 by incorporating the digests of Kennedy 3. One would have been motivated to make the modification because the methods of Kennedy 1 and Kennedy 2 identify a molecule’s methylation level by partitioning and the sensitivity and specificity of the method is challenged by methylated/unmethylated molecules partitioning incorrectly (e.g. unmethylated molecules partitioning into the hyper partitioned set). Kennedy 3 further teaches in order to increase the signal to noise ratio of a methylation partitioning assay, specific partitioned sets can be subjected to a methylation-sensitive restriction enzyme (RE) digestion reaction to specifically remove the incorrectly partitioned molecules. See para. 149.
Claim(s) 120-121 and 123 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kennedy 1 (WO 2018/119452 A2) in view of Kennedy 2 (US 2018/0305738 A1) and Lai (Genome Res. 2013. 23:2030-2041 and Supplemental Material) as applied to claim 104 above and in further view of Koestler (Cancer Epidemiol Biomarkers Prev. 2017. 26(3):328-338).
Regarding claims 120, 121 and 123, the combination of Kennedy 1, Kennedy 2 and Lai renders obvious the elements of claim 104 as described above and as required by claims 120, 121 and 123.
The combination does not teach the additional elements specific to claims 120-121 and 123.
However, Koestler teaches DMRs for immune cells and analyses useful for cancer evaluation based on the amount of cells.
Regarding claim 120, Koestler identifies DMRs for immune cells including NK cells (p. 4, 5, 8 and 9).
Regarding claims 121 and 123, Koestler teaches determining the levels of cells, such as neutrophils, relative to total blood lymphocytes in a mdNLR (p. 3).
It would have been prima facie obvious to the ordinary artisan to have modified the method of Kennedy 1 and 2 by including DMRs for other immune cells, including NK cell and neutrophils, because they provide information that is useful in determining ratio relevant to cancer information (p. 2 of Koestler).
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.
Claim 104-123 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 6-8, 10, 12-13, 20-23, 25-26, 32-34, 41, 46, 70, 72 and 89 of copending Application No. 19/085,589 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claim sets both are based on partitioning DNA based on modified cytosine content, capturing partitioned DNA that is differentially methylated between immune cell types and sequencing the captured DNA.
Any elements of the present claims not required by the ‘589 claims are rendered obvious in view of the teachings of Kennedy 1, Kennedy 2, Kennedy 3, Lai and Koestler as described above.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH G DAUNER whose telephone number is (571)270-3574. The examiner can normally be reached 7 am EST to 4:30 EST with second Fridays Off.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Winston Shen can be reached at 5712723157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JOSEPH G. DAUNER/ Primary Examiner, Art Unit 1682