DETAILED CORRESPONDENCE
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 .
This action is in response to the papers filed April 2, 2026. Currently, claims 15-16, 21-34 are pending.
All arguments have been thoroughly reviewed but are deemed non-persuasive for the reasons which follow. This action is made FINAL.
Any objections and rejections not reiterated below are hereby withdrawn.
The 101 rejection over the products has been withdrawn in view of the amendments to the claims to require particular probes with particular labels.
The 102 rejection over NEB has been withdrawn in view of the amendment to require particular 5’ and 3’ labels.
Priority
This application is a 371 of PCT/CN2021/110526 filed August 4, 2021.
Claim Rejections - 35 USC § 101- Methods
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 30-34 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.
Question 1
The claimed invention is directed to a process that involves a natural principle and a judicial exception.
Question 2A Prong I
The claims are taken to be directed to an abstract idea, a mathematical relationship and mathematical calculation.
Claims 30-34 are directed to “a method for detecting an expression level of HRH4” using a standard curve constructed by a standard. Claim 34 provides the standard cure is a simple mathematical calculation using multiplication and addition.
The standard curve is an arithmetic calculation to generate an expression level and so falls into the “mathematical concepts” grouping of abstract ideas.
Question 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. While the claim recites preparing RNA extracted from a sample and performing real-time PCR, this is not an integration of the exception into a practical application. Instead, these elements are data gathering required to perform the method. Thus, the claim is “directed to” the exception.
Question 2B
The second step of Alice involves determining whether the remaining elements, either in isolation or combination with the other non patent ineligible elements, are sufficient to “’transform the nature of the claim’ 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 from a statement of a natural principle for at least these reasons:
The claims do not include applying the judicial exception, or by use of, a particular machine. The claims do not tie the steps to a “particular machine" and therefore do not meet the machine or transformation test on these grounds. The use of machines generally does not impose a meaningful limit on claim scope.
The claims also do not add a specific limitation other than what is well-understood, routine and conventional in the field. The measuring expression using RT-PCR is mere data gathering step that amounts to extra solution activity to the judicial exception. It merely tells the users of the method to determine expression levels of HRH4 of a sample without further specification as to how the sample should be analyzed. The claim does not recite a new, innovative method for such determination. The determining step essentially tells users to determine the markers through whatever known processes they wish to use.
Further it is noted that the courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014)
For these reasons the claims are rejected under section 101 as being directed to non-statutory subject matter.
Response to Arguments
The response traverses the rejection. The response asserts the claims do not recite a judicial exception. This argument has been considered but is not convincing because the “determining the expression level of HRH4 mRNA using a standard curve constructed by a standard” is a judicial exception. This standard curve is a mathematical concept. Thus, the claim recites a judicial exception.
The steps in addition to the judicial exception are preparing a reaction system, conducting qRT-PCR. The response argues that the claim requires specific primer/probe sequences, specific concentrations and specific enzyme mixtures. First, Claim 30 is not directed to particular primers/probes. Instead the claims are directed to sequences or fragments within the sequences or sequences comprising the SEQ ID NO:. Thus, no particular sequence is claimed. Second, Claim 30, 31 do not require any particular concentrations or mixtures. Applicant may wish to clarify the claims to reflect their arguments.
The response argues that the claims are significantly more because they are an improvement to the technology however the response does not provide what the improvement is. The response asserts the combination of specific conditions is an improvement however the response provides no evidence of the improvement.
Thus for the reasons above and those already of record, the rejection is maintained.
Claim Rejections - 35 USC § 112- Second Paragraph
The following is a quotation of 35 U.S.C. 112(b):
(B) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 15-16, 21-34 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 pre-AIA the applicant regards as the invention.
The claims are directed to “a nucleotide sequence shown in” SEQ ID NO: 1-3. It is unclear what the transition “a nucleotide sequence shown in” encompasses. It is unclear whether the claim requires a nucleic acid comprising SEQ ID NO: 1-3 or whether the claim encompasses any nucleic acid within SEQ ID NO: 1-3, such that the claim encompasses any fragments. Clarification is required.
Response to Arguments
The response traverses the rejection. The response asserts claims 15-16 have been amended to replace “shown in” with “as set forth”. This argument has been considered but is not convincing because Claim 24 remains directed to “shown in”.
The new language of “a first primer having a nucleotide sequence as set forth SEQ ID NO: 1” has similar indefiniteness because it is unclear whether all of SEQ ID NO: 1 is required or a fragment from within SEQ ID NO: 1 is encompassed. Applicant may wish to consider amending the claims to recite “the HRH4-F comprises the nucleotide sequence of SEQ ID NO: 1”, for example.
Thus, for the reasons above and those already of record, the rejection is maintained.
Claim 29 is indefinite because it is unclear what an RNA standard encompasses in a kit. A standard is not a “thing” therefore it is unclear how it can be included in a kit. A standard, as defined by the specification, appears to be an equation for a calculation. It is unclear how this may be included in a kit.
Response to Arguments
The response traverses the rejection. The response asserts an RNA standard is a standardized RNA solution of HRH4 which refers to a physical entity with a known concentration and not an equation for a calculation. This argument has been reviewed but is not persuasive. The response does not point to any limiting definition in the specification or the claims such that the claims are limited as argued. Thus, for the reasons above and those already of record, the rejection is maintained.
Claims 16, 22 and 25 has been amended to require the H4 probe and the G-probe are labeled with the same quenching or different quenching groups. Claim 15 requires the 3’end of the H4 probe is labeled with BHQ1. Claim 16 requires the 3’ end of the G-Probe is labeled with BHQ1. Therefore, it is unclear how these probes can be labeled with different quenching groups. Claim 25 is similarly unclear. Clarification and correction are required.
Claims 25, 27 are indefinite over the recitation G-probe and the GAPDH-F, the GAPDH-R and the G-probe because Claim 23 and Claim 15 from which they depend do not recite G-probe of GAPDH sequences. The oligonucleotides lack proper antecedent basis.
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.
Claim 26 is 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 15 has been amended to require “the fluorescent reporter is FMA or Joe and the quencher is BHQ1. Claim 26 does not add any additional limitations. The claims are identical in scope. 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
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 15-16, 30-34 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fang et al. (BMC Cancer, Vol. 11, No. 195, 2011) in view of Gallagher et al. (US 7,164,003, January 16, 2007) and Untergasser et al. (Primer3Plus, an enhanced web interface to Primer3, Nucleic Acids Research, 2007, Vol. 35, 2007) and further in view of Soltany-Rezaee-Rad (Biologicals, Vol. 32, pages 130-135, 2015) and Tsybulsky et al. (Molecular and Cellular probes, Vol. 30, pages 2385-290, 2016).
Fang teaches expression of HRH4 in colorectal carcinomas. Fang teaches RT-PCR and real-time quantitative PCR. Total RNA was reverse transcribed real-time PCR and TR-PCR with gene specific primers was performed. The real-time PCR was performed with Real-time PCR Master Mix containing SYBR GREEN I and hot-start Taq DNA polymerase. GAPDH was amplified as a control.
Fang does not specifically teach the primers and probes of SEQ ID NO: 1-6 for HRH4 and GAPDH.
However, Gallagher teaches histamine receptor H4 polynucleotides. SEQ ID NO: 1 of Gallagher comprises SEQ ID NO: 1, 2, and 3 of the instant application.
Soltany-Rezaee-Rad teaches comparison of SYBR Green and TaqMan real-time PCR methods for quantitative detection of DNA. Soltany-Rezaee-Rad teaches the LOD of the SYBR green and TaqMan assays showed TaqMan assay had a better sensitivity than the SYBR Green (abstract). Soltany-Rezaee-Rad also teaches PrimerSelect software may be used to design appropriate primers for TaqMan and provides the primers and probe in Table 1.
Tsybulsky teaches various molecular beacons with JOE dye and BHQ1 for usability at different temperatures and detection conditions.
It would have been prima facie obvious prior to the effective filing date of the claimed invention to have modified the quantitative method of Fang with a Taq-Man assay using primers and probes with Joe and BHQ1 reporter/quencher pairs. The ordinary artisan would have been motivated to have modified the real-time quantitative PCR method of Fang with the TaqMan process because Soltany-Rezaee-Rad teaches TaqMan has better sensitivity than the SYBR gene method.
Further, a skilled artisan at the time of filing would have designed primers and probes to known sequences (such as the sequences disclosed in the above references) with a high expectation of success. To design such primers constituted routine and conventional optimization at the time of filing. See In re Aller, 220 F.2d 454, at 456 (CCAP 1955) (“where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.”). Numerous references describe how to design and optimize primers and probes for PCR applications. For example, Untergasser teaches how to design primers and probes from known sequences using known online primer/probe design programs for use in PCR assays. Untergasser teaches how to use Primer3Plus online program to design primers and probes to known sequences (Untergasser at pgs. W71-74). In other words, Untergasser provides specific guidance and parameters to optimize primer, probe and PCR assay design to yield optimal results; thus, designing PCR assays for particular applications constitutes well-known routine optimization. Selection of specific oligonucleotides for specific Tm represents routine optimization with regard to sequence, length and composition of the oligonucleotide. Such optimization parameters are explicitly recognized in Untergasser. Soltany-Rezaee-Rad also teaches PrimerSelect software may be used to design appropriate primers for TaqMan and provides the primers and probe in Table 1. As noted in In re Aller, 105 USPQ 233 at 235, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Routine optimization is not considered inventive and no evidence has been presented that the primer selection performed was other than routine, that the products resulting from the optimization have any unexpected properties, or that the results should be considered unexpected in any way as compared to the closest prior art.
Thus, the instant sequences are clearly a functional homologues of the above similar primers based on the known HRH4 sequence. This is supported by In Re Deuel, 34 USPQ 2d 1210 (Fed. Cir. 1995), in which the Court of Appeals for the Federal Circuit stated that (emphasis added),
Normally, a prima facie case of obviousness is based upon structural similarity, i.e., an established structural relationship between a prior art compound and the claimed compound. Structural relationships may provide the requisite motivation or suggestion to modify known compounds to obtain new compounds. The claimed sequences were structural homologs of the sequences disclosed in the prior art, and concerning which a biochemist of ordinary skill would attempt to obtain alternate compounds with improved properties. Therefore, the claimed sequences are prima facie obvious over the cited references in the absence of secondary considerations.
The ordinary artisan would have had a reasonable expectation of success that such primers generated using known sequences as taught by Fang and Gallagher to detect the same HRH4 because the claimed probes are functional equivalents of the sequences. The ordinary artisan would have been motivated to generate a number of said primers to the same HRH4 sequence to provide flexibility and optimize experimentation (see Untergasser). Selection of specific oligonucleotides for specific Tm represents routine optimization with regard to sequence, length and composition of the oligonucleotide. Such optimization parameters are explicitly recognized in Untergasser. As noted in In re Aller, 105 USPQ 233 at 235, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Routine optimization is not considered inventive and no evidence has been presented that the primer selection performed was other than routine, that the products resulting from the optimization have any unexpected properties, or that the results should be considered unexpected in any way as compared to the closest prior art.
In sum, the claimed primers are prima facie obvious because there was clear motivation to design PCR primers to detect the same HRH4 sequence; and designing and optimizing such primers constitutes a well-known, routine and conventional technique which would yield the claimed primers with a reasonable expectation of success.
Applicants should submit secondary evidence of non-obviousness in line with MPEP §§ 716.01-716.02 (e.g. unexpected results evidence).
With regard to claim 34, the references do not give precise standard curve equation. However, it has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980). One skilled in the art would have known to use standards to establish standards for determining the expression level of a gene. Thus, the recited standard of the claims would be arrived at by routine experimentation by one of ordinary skill in this art.
Response to Arguments
The response traverses the rejection. The response asserts Claim 15 was amended to incorporate the features of Claim 17-18. This argument has been considered but is not convincing because old Claim 17 requires the probes are labeled with different reporter groups. Newly amended Claim 15 does not require this limitation so the limitations were not merely added to Claim 15 to overcome the rejection.
The response argues the references do not teach the HRH4 primers and probe with the particular labels. This argument has been reviewed but is not persuasive. The art is replete with teaching of the use of commercially available computer programs to input sequences of the target to generate primers and probes, including TaqMan primers and probes. The use of a computer program to design primers and probes is not inventive. It is mere routine experimentation to ask a computer to design and select primers/probes for analysis.
The response appears to argue unexpected results in Comparative Examples 1 and 2 of the application (see para 86 and 92). Comparative Example 1 compares SEQ ID NO: 1-3 with SEQ ID NO: 7-9.
An alignment of the HRH4 gene and SEQ ID NO: 1-3, 7-9 was performed.
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It is unclear where SEQ ID NO: 7-9 hybridize to the HRH4 gene because the primers did not match the HRH4 sequence of NM_021624.4. If Applicant wishes to provide unexpected results for SEQ ID NO: 1-3, clarification of where SEQ ID NO: 7-9 bind is required to determine if these are a comparison to the closest prior art.
Further, if the comparison is performed to primers consisting of SEQ ID NO: 1-3, the instant claims are not commensurate in scope with the unexpected results because the primers are any sequence from within SEQ ID NO: 1-3 (set forth in) and primers comprising SEQ I DNO: 1-3 and larger. As provided MPEP 716.02(d) requires the unexpected results are commensurate in scope with the claims.
Even more, comparative Example 2 provides that particular ratio of enzyme mixed solutions were used and the best ratio of enzyme mixed solution is shown in Figure 7B. The instant claims are not commensurate in scope with these best results or unexpected results.
Table 5 of the specification compares TaqMan to an ELISA assay. This is not a comparison of the closest prior art. The art cited in the instant action is closer prior art. Fang teaches primers for HRH4 (see top of page 3). Thus, this comparison is not persuasive to overcome the obviousness rejection of record.
The response does not separately argue Claim 16 or 30-34. Thus, the rejections are maintained for the reasons above. Thus, for the reasons above and those already of record, the rejection is maintained.
Conclusion
No claims allowable.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Nguyen et al. (Molecular Pharmacology, Vol. 59, No. 3, pages 427-433, 2001) teaches characterization of the H4 receptors. Figure 1 provides an alignment of the histamine receptors H1-H4. Nguyen teaches amplifying three overlapping fragments (A, B, and C) and provides the primers.
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 JEANINE ANNE GOLDBERG whose telephone number is (571)272-0743. The examiner can normally be reached Monday-Friday 6am-3:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng (Winston) Shen can be reached on (571) 272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JEANINE A GOLDBERG/Primary Examiner, Art Unit 1682
April 25, 2026
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