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 .
Effective Filing Date
The present application, filed on January 28, 2022, is a 371 of PCT/CN2020/105047, filed on July 28, 2020 and claims foreign priority to CHINA 2019 10695955.6, filed on July 30, 2019. A certified copy of the foreign priority document was filed on January 28, 2022, however, it is noted that no certified translation of the priority document has been provided. Therefore, the effective filing date of the present application is determined to be July 28, 2020.
Election/Restrictions
Applicant’s election with traverse of: the invention of Group II encompassing claims 6-8 and 15, the “combination of at least Hm 13 (Z19) and Nhp2L1 (Z21)” as the elected species of the genus “a single combination of at least two imprinted genes”, and “mammary cancer” as the elected species of the genus “tumor type” in the reply filed on April 25, 2025 is acknowledged.
The traversal is “on the ground that Applicant disagrees with the Examiner’s interpretation of the reference Miettinen.” The response argues that Miettinen “does not disclose the use of the different expressions… of the imprinted gene GATA3 in tumor diagnosis, let alone its combination with other recited imprinted genes in tumor diagnosis”. The response further argues that Z19 and Z21 are “special technical features” not disclosed in Miettinen.
These arguments have been thoroughly reviewed, but are not persuasive for the following reasons:
Regarding the argument that the combination of the imprinted genes Z19 and Z21 “are a special technical feature”, the broadest reasonable interpretation of the claims as presented encompasses a method for carrying out tumor diagnosis by analyzing expression of a tumor marker comprising any one of imprinted genes Z17-Z28. Z18 is GATA3. The required technical feature shared among all of the claims is “a tumor marker comprising any one imprinted gene…”. Therefore, a showing of lack of unity among the claims a posteriori requires only a showing that “a tumor marker comprising any one of [the list of recited imprinted genes]” was known in the art prior to the effective filing date of the claimed invention.
Regarding the argument that Miettinen does not disclose the use of different expressions of the imprinted gene GATA3 in tumor diagnosis, let alone its combination with other recited genes, Miettinen teaches measuring GATA3 expression (one of the recited imprinted genes) in normal developing and adult tissues and in thousands of neoplasms using immunohistochemistry (Miettinen et al., abstract). Furthermore, Miettinen specifically teaches “GATA3 was expressed in >90% of primary and metastatic ductal and lobular carcinomas of the breast, urothelial, and cutaneous basal cell carcinomas and trophoblastic and endodermal sinus tumors and was more sensitive for metastatic breast carcinomas than the established marker GCDFP (Miettinen, Abstract). Therefore, the shared technical feature “a tumor marker comprising any one of imprinted genes Z17-Z28” is not a special technical feature.
Therefore, the requirement is still deemed proper and is therefore made FINAL.
Claim Status/Action Summary
This action is in response to the papers filed September 16, 2025.
Claims 1-6, 9-14 are pending in the present application. Claims 7-8 and 15 were canceled in the response to nonfinal rejection.
Claims 1-5, and 9-14 are withdrawn as directed to a non-elected invention.
Claim 6 is under examination.
Any objections and rejections not reiterated below are hereby withdrawn.
The objections to the specification have been withdrawn in view of the substitute specification filed September 16, 2025.
The objection to claim 6 as being an improper multiple dependent claim has been withdrawn in view of the amendment to put the claim into independent form.
The rejections of record under U.S.C. 112(b) have been withdrawn in view of the claim amendments canceling claims 7, 8, and 15, and requiring that analysis of gene expression in claim 6 comprises in situ hybridization.
The rejection of record under U.S.C. 112(d) has been withdrawn in view of the amendments to the claims.
The rejection of record under U.S.C. 102(a)(1) over Lindahl et al. has been withdrawn in view of amendments to the claims requiring that the analysis of expression comprises performing in situ hybridization.
Claim Objections
Claim 6 is objected to because of the following informalities: Apparent typographical issue at line 3: “…genes of a tumor marker of in a sample…”. Appropriate correction is required.
This is a new objection necessitated by the amendments to the claims.
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.
Claims 6 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 6 is indefinite because the claim recites the limitation "said subject in need of treatment". There is insufficient antecedent basis for this limitation in the claim. Claim 6 recites antecedent basis for “a subject” and that mammary tissue and/or cell sample taken from the subject may be determined as healthy, having a loss of imprinting and/or copy number variation determined as a mammary cancer tissue and/or cell sample. However, there is no recitation of “a subject in need of treatment” and it is unclear whether the sampling is intended to exclude samples derived from previous surgical interventions/archived tissues wherein the subject from which the sample was obtained is no longer in need of treatment (i.e. the surgical procedure was successful in removing all of the tumor or the subject is no longer alive).
This is a new rejection necessitated by the amendments to the claims.
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.
Claim 6 is rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
This rejection has been updated as necessitated by the amendments to the claims.
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 I
The claimed invention is directed to a process that involves a natural principle and judicial exceptions.
Step 2A Prong I
The claims are taken to be directed to a natural phenomenon and abstract ideas.
Claim 6 is directed to “a tumor diagnosis model for carrying out tumor diagnosis by analyzing expression of [recited imprinted genes]” (i.e. a method of tumor diagnosis by analyzing the expression of a set of genes).
Claim 6 is directed to a process that involves the judicial exception of a law of nature/natural phenomenon (i.e. the natural correlation between the expression (or lack thereof) of certain genes due to loss of imprinting or copy number variation (duplication) of the genes in question and the presence of a tumor).
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exceptions for the reasons that follow.
A correlation that preexists in the human is an unpatentable phenomenon. The association between expression of imprinted genes and presence of mammary cancer is a law of nature/natural phenomenon. The “analyzing” and “determining” steps recited by claim 6 which tell users of the process to determine that a mammary tissue and/or cell sample is a mammary cancer tissue and/or cell sample amounts to no more than an “instruction to apply the natural law”. These “analyzing” and “determining” steps amount to no more than mental steps. Even if the step requires something more such as to verbalize the discovery of the natural law, this mere verbalization is not an application of the law of nature to a new and useful end. The “analyzing” and “determining” steps do not require the process user to do anything in light of the correlation. These steps fail to provide the “practical assurance” sought by the Prometheus Court that the “process is more than a drafting effort designed to monopolize the law of nature itself.”
Step 2A Prong II
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. Claim 6 recites “performing in situ hybridization of a probe designed based on the sequence of an intron…” However, this step is not an integration of the exception into a practical application. Instead, this step constitutes extra-solution activity necessary to gather data necessary to perform the method.
Claim 6 further recites “treating [a] subject in need of treatment by administration of medication or other treatment in accordance with the determined status of said tumor”. However, this step is not an integration of the exception into a practical application. This step recites treating a subject conditional upon an observation of the natural correlation and thus encompasses embodiments wherein no treatment is required/administered. Therefore, this step does not require the process user to do anything in light of the correlation in embodiments wherein the sample is determined to be a healthy tissue and/or cell sample. Furthermore, the claim does not require the administration of any particular “medication or other treatment” to the subject and therefore does not practically limit the scope of the claims in any meaningful way as “medication or other treatment” encompasses, for example, at least: any chemotherapy, any immunotherapy, any surgical intervention, any radiotherapy, any method comprising palliative care, any counseling, etc. This step is therefore not an integration of the exception into a practical application. Instead, this element amounts to a mere invitation to the skilled artisan to apply the judicial exception to a general field of use.
Accordingly, the claims are directed to judicial exceptions.
Step 2B
The second step of Alice involves determining whether the remaining elements, either in isolation or combination with the other non-patent eligible elements, are sufficient to “transform the nature of the claims into a patent eligible application” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
The claims are not sufficiently defined to provide a method which is significantly more than a statement of a natural principle for at least these reasons:
The claims also do not add a specific limitation other than what is well-understood, routine, and conventional in the field.
The claims require analyzing the expression of certain genes comprising performing in situ hybridization of a probe designed based on the sequence of an intron of an imprinted gene with cells of the sample and staining the sample with a staining chemical.
The claim does not recite a new, innovative method for such determination. Conducting gene expression analysis by in situ hybridization using probes designed based on the sequence of an intron of an imprinted gene was well known in the art at the time the invention was made. The steps are recited at a high level of generality. The prior art, for example, Bonthuis et al., “Noncanonical Genomic Imprinting Effects in Offspring” Cell Reports 12, 979-991 (published August 11, 2015), teaches methods comprising measuring expression of imprinted genes in cells wherein the cells are counterstained and microscope images are analyzed to determine the imprinting status of the genes (Bonthuis et al., 2015, figure 6, excerpt below).
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Furthermore, the instant specification states that “In this application, the probes for use in the in-situ hybridization are designed according to the sequences of the imprinted genes to be detected… a sequence is selected from the intron of each of the to-be-detected genes as the corresponding probe. The probes used in this application were designed by Advanced Cell Diagnostics.” (i.e. the design of said probes is available as a commercial service from a company). Therefore, the use and design of said probes are routine and conventional steps well-known in the relevant field.
For these reasons, the claims are rejected under section 101 as being directed to non-statutory subject matter.
Response to arguments
The response states “Applicant respectfully submits that the amended claim 6 is directed to patent eligible subject matter.” This assertion has been thoroughly reviewed, but is not persuasive.
The updated rejection above details that the newly added limitations “comprising in situ hybridization with a probe designed based on the sequence of an intron…” and “treating said subject in need of treatment by administration of medication or other treatment in accordance with the determined status of said tumor” do not integrate the identified judicial exceptions into a practical application of the exception that is significantly more than a statement of a natural principle and do not transform the nature of the claims into a patent-eligible application.
Claim Rejections - 35 USC § 103
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.
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.
Claims 6 is rejected under 35 U.S.C. 103 as being unpatentable over Lindahl et al., US 20120295815 A1, published November 22, 2012 in view of Goovaerts et al., “A comprehensive overview of genomic imprinting in breast and its deregulation in cancer”, Nature Communications (2018)9:4120 and Bonthuis et al., “Noncanonical Genomic Imprinting Effects in Offspring” Cell Reports 12, 979-991 (published August 11, 2015).
This is a new grounds of rejection necessitated by the claim amendments.
Regarding claim 6, Lindahl et al. teach a method comprising diagnosing breast cancer by analyzing the expression of a panel of genes (Lindahl et al., paragraphs 0012-0015 and 0080-0085 including the elected species Z21 (NHP2L1) (corresponds to probe number 916 in table 5, represented in 80% of cancer samples assayed) (Lindahl et al., table 5, page 64) and Z19 (HM13) (corresponds to probe number 1129, represented in 90% of cancer samples assayed) (Lindahl et al., table 5, page 75). Lindahl et al. further teach methods comprising treating an individual with cancer by surgery, radiation, and/or chemotherapy (Lindahl et al., paragraph 0140).
Lindahl et al. do not teach that the expression of NHP2L1 and HM13 are analyzed by a method comprising in situ hybridization of a probe designed based on the sequence of an intron or that the cancer related differences in expression of the genes Z19 (HM13) and Z21 (NHP2L1) are regulated by imprinting (DNA methylation/parent-of-origin specific gene silencing).
However, Goovaerts et al. teaches that breast cancer is characterized by massive deregulation of imprinting as well as copy number variation and aberrant DNA methylation (Goovaerts et al., abstract), and that HM13 is an exemplary imprinted gene that exhibits different expression in breast cancer due to loss of imprinting.
Additionally, Bonthuis et al. teaches methods comprising measuring expression of imprinted genes in cells wherein the cells are counterstained with Hematoxylin (i.e. a staining chemical) and microscope images are analyzed to determine the imprinting status of the genes (Bonthuis et al., 2015, figure 6, excerpt below). Bonthuis et al. teach a method for designing in situ hybridization probes based on the sequence of rapidly processed introns that can “resolve allelic expression at the cellular level for any gene” (Bonthuis et al., page 986, column 1).
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Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to analyze expression of the recited genes to diagnose and treat breast cancer, as taught by Lindahl et al., based on differences in expression are due to loss of imprinting, copy number variation, and/or aberrant DNA methylation, as taught by Goovaerts et al, as measured by the molecular technique comprising in situ hybridization of probes for determining imprinting status designed based upon the sequence of introns in any gene, as taught by Bonthuis et al.
The ordinary artisan would have been motivated to determine the differences in gene expression are due to loss of imprinting or copy number variation because of the teaching of Goovaerts et al. that imprinting is generally deregulated in breast cancer (Goovaerts et al., abstract) and that imprinting deregulation is associated with cancer development (Goovaerts et al., page 9, paragraph 1). The ordinary artisan would likewise have been motivated to utilize the method comprising in situ hybridization with intronic target sequences by the express teachings of Bonthuis et al. that their method of probe design allows for identification of allelic expression (i.e. imprinting status) at the cellular level for any gene.
The ordinary artisan would have been reasonably confident that the method of diagnosing breast cancer by analyzing the expression of a panel of genes comprising HM13 and NHP2L1, taught by Lindahl et al., by the method comprising in situ hybridization of probes to introns of any particular gene, taught by Bonthuis et al., would have further detected that differences in expression of HM13 and NHP2L1 are due to changes in regulation of the genes at the level of imprinting, as taught by Goovaerts et al.
Response to arguments
The response argues that the previously cited prior art does not teach all of the limitations of the claim as amended comprising “image analysis of stained nucleus of sample cells for visualizing nascent RNA from which the RNA expression status of the imprinted genes is assessed”. This argument has been thoroughly reviewed, but is not persuasive. The claim as amended is rejected under the new 103 rejection above. As is discussed above, the newly incorporated limitations regarding a specific nascent RNA visualization technique “performing in situ hybridization of a probe designed based on the sequence of an intron of an imprinted gene… and staining… with a staining chemical… and analyzing microscopic images of the stained sample” are taught in the prior art by at least Bonthuis et al. and, taken together with the teachings of Lindahl et al. and Goovaerts et al., would have been obvious to one of ordinary skill in the art for the claimed purpose as detailed in the 103 rejection above.
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 6 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18/650,140 (herein referred to as ‘140) in view of Bonthuis et al., “Noncanonical Genomic Imprinting Effects in Offspring” Cell Reports 12, 979-991 (published August 11, 2015). Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
This rejection has been updated as necessitated by the amendments to the present claims.
Regarding claim 6, the claims of ‘140 recite a grading model of gene expression status for a tumor (i.e. method for carrying out tumor diagnosis…) comprising calculating changes in a total expression, single-allelic expression, bi-allelic expression, and multi-allelic expression (i.e. analyzing expression… as not being expressed, having a loss of imprinting, or having a copy number variation) of the imprinted genes HM13 (Z19) and SNU13 (i.e. Nhp2L1, Z21) (‘140, claim 1). Bonthuis et al. teaches methods comprising measuring expression of imprinted genes in cells wherein the cells are counterstained with Hematoxylin (i.e. a staining chemical) and microscope images are analyzed to determine the imprinting status of the genes (Bonthuis et al., 2015, figure 6, excerpt below). Bonthuis et al. teach a method for designing in situ hybridization probes based on the sequence of rapidly processed introns that can “resolve allelic expression at the cellular level for any gene” (Bonthuis et al., page 986, column 1).
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Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to analyze expression of the recited genes to diagnose and treat breast cancer based on differences in expression are due to loss of imprinting, copy number variation, and/or aberrant DNA methylation, recited by the claims of ‘140, as measured by the molecular technique comprising in situ hybridization of probes for determining imprinting status designed based upon the sequence of introns in any gene, as taught by Bonthuis et al.
The ordinary artisan would have been motivated to utilize the method comprising in situ hybridization with intronic target sequences by the express teachings of Bonthuis et al. that their method of probe design allows for identification of allelic expression (i.e. imprinting status) at the cellular level for any gene.
The ordinary artisan would have been reasonably confident that the method of diagnosing breast cancer by analyzing the expression of a panel of genes comprising HM13 and NHP2L1, recited by the claims of ‘140, by the method comprising in situ hybridization of probes to introns of any particular gene, taught by Bonthuis et al., would have successfully assessed the expression level/status of the claimed genes.
Response to arguments
The response states: “Applicant respectfully requests that this rejection be held in abeyance until allowable subject matter in this application is found or indicated, upon which time Applicant will consider, if appropriate, a terminal disclaimer to obviate this rejection.
This request has been noted and is denied.
See MPEP 804(I)(b)(1) and 37 C.F.R. 1.111(b), which allows that some objections may be held in abeyance, but includes no provision for holding rejections in abeyance. Thus, for the reasons above and those already of record, the rejection is maintained.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY MARK TURPIN whose telephone number is (703)756-5917. The examiner can normally be reached Monday-Friday 8:00 am - 5:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, 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.
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/Z.M.T./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682