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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 March 8, 2026. Currently, claims 14-32 are pending. Claims 28-32 have been withdrawn from consideration as directed to non-elected subject matter.
Priority
This application is a 371 of PCT/CN2021/110526 filed August 4, 2021.
Election/Restrictions
Applicant's election without traverse of Group I, Claims 14-27 in the paper filed March 8, 2026 is acknowledged.
The requirement is still deemed proper and is therefore made FINAL.
Objections
The claim set comprises 2 claims numbered 24. One of the Claim 24’s is cancelled. However, as provided by 1.126, “The original numbering of the claims must be preserved throughout the prosecution. When claims are canceled the remaining claims must not be renumbered. When claims are added, they must be numbered by the applicant consecutively beginning with the number next following the highest numbered claim previously presented (whether entered or not).” Applicant should renumber the 2nd Claim 24 as claim 25 and claim 25+ should be renumbered as 26+ to comply with the rules.
Claim Rejections - 35 USC § 101- Products
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 14-15, 20-21, 24, 27 are rejected under 35 U.S.C. 101 because the claimed invention is not directed to patent eligible subject matter. Based upon an analysis with respect to the claim as a whole, the rejected claim(s) do not recite something significantly different than a judicial exception. The rationale for this determination is explained below:
Briefly, 14-15, 20-21, 24, 27 are rejected because these claims are drawn to a nucleic acid molecule “shown in” SEQ ID NO: 1-6.
The claims are directed to nucleic acid fragments from the human genome, i.e. known naturally occurring nucleic acids. Such isolated nucleic acid molecules, that are identical to fragments of naturally occurring nucleic acid molecules are not patent eligible subject matter, i.e. they are judicial exceptions to patentable subject matter.
Claim 24 is directed to the naturally occurring fragments ad particular concentrations. These concentrations do not change the eligibility of the naturally occurring nucleic acids.
Claim 27 is directed to the naturally occurring nucleic acids in a kit with buffers, dye and water. The claims do not require the dye is irreversibly attached to the nucleic acids. Instead, the claim merely requires the elements in separate vials. Given the broadest reasonable interpretation, these additional reagents are enzymes that are naturally occurring. The claimed primers and probe are identical to fragments of naturally occurring genes. This does not change the patent eligibility of the naturally occurring nucleic acids.
MPEP 2106.04(b)(II) discusses products of nature. The MPEP specifically discusses DNA, primers and probes. The isolated DNA of Myriad and the primers of Ambry Genetics were described as products of nature by the courts. Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 133 S. Ct. 2107, 2116-17, 106 USPQ2d 1972, 1979 (2013); University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 758-59, 113 USPQ2d 1241, 1243 (Fed. Cir. 2014). The MPEP further states the “product of nature exceptions include both naturally occurring products and non-naturally occurring products that lack markedly different characteristics from any naturally occurring counterpart. See, e.g., Ambry Genetics, 774 F.3d at 760, 113 USPQ2d at 1244 ("Contrary to Myriad's argument, it makes no difference that the identified gene sequences are synthetically replicated. As the Supreme Court made clear, neither naturally occurring compositions of matter, nor synthetically created compositions that are structurally identical to the naturally occurring compositions, are patent eligible.").” The Federal Circuit in Ambry Genetics reviewed “[t]he Supreme Court held ineligible claims directed to segments as short as 15 nucleotides, the same length as the primer claims at issue here, suggesting that even short strands identical to those found in nature are not patent eligible. Compare ’492 patent col. 170 ll. 32–38, with ’282 patent col. 153 ll. 66–67.”
In the instant case, the claims, embrace probes and primers that are identical to naturally occurring gene fragments and clearly read on nature-based products that themselves do not exhibit markedly different characteristics from the naturally occurring gene. See e.g. Myriad in which one claim at issue was drawn to “[a]n isolated DNA having at least 15 nucleotides [an isolated DNA coding for a BRCA1 polypeptide having the amino acid sequence of SEQ ID NO: 2] (Myriad at 2113). The Court recognized that this claim, if valid, would have given Myriad exclusive right to isolate any strand of 15 or more nucleotides of an individual’s BRCA1 gene (paragraph bridging 2113 and 2114). This is directly analogous to the instant situation wherein Applicant’s claims cover probe and primer molecules that are fragments of a naturally occurring human genome sequence. The Court held that “[a] naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated”, and that “Myriad’s claims are not saved by the fact that isolating DNA from the human genome severs the chemical bonds that bind gene molecules together” (page 2118). The Court found that while Myriad had located and sequenced an important gene, Myriad had not created anything, and that “separating that gene from its surrounding genetic material is not an act of invention” (page 2118). Consistent with the findings of the Court in Myriad, the Office finds that the primers and probe molecules embraced by the instant clams are not patent eligible compositions of matter regardless of whether or not they are isolated from the genome. The Guidelines indicate that a change in biological function or activity maybe a characteristic of an isolated product that can provide a marked difference sufficient to distinguish over a naturally occurring product. However, in this case, as in the Ambry case, the function of the nucleic acids is the same function as the relevant portion of the naturally occurring sequence. Just as in nature, primers and probes utilize the innate ability of DNA to bind to itself.
Having established that the claims include a naturally occurring product that is a judicial exception, it must now be determined whether or not the claims recite an element or combination of elements that amount to significantly more than that exception, and whether those additional elements also amount to significantly more for the other claimed exception(s), which ensures that the claim does not have a preemptive effect with respect to any of the recited exceptions. To determine whether a claim that includes a nature-based product limitation recites a “product of nature” exception, an analysis is performed in which it is first determined if a claim includes a nature-based product that has markedly different characteristics from the corresponding naturally occurring product, and if it does not, then it is determined whether or not other elements of the claim are sufficient to ensure that the claim as a whole amounts to significantly more than the exception itself (see the Interim Guidance on Patent Subject Matter Eligibility published 12/16/2014 in the Federal Register at pages 74618-74633). In order to be markedly different the claimed product must possess at least one characteristic that is different from that of the counterpart.
In the instant case, any additional element, i.e. buffers, reaction tubes, containers, vials do not overcome the naturally occurring product exception. None of these limitations provides any significant addition to the judicial exceptions already claimed that would prevent the claims from having a pre-emptive effect on the use of the judicial exception. The presence of a “tube" in a composition comprising a nucleic acid is entirely conventional and does not represent a modification that amounts to something significantly more than the judicial exception.
The fact that these natural products are organized into a kit with an intended use adds nothing to the judicial exceptions that would distinguish them from the naturally occurring material. Therefore, the claims are properly rejected under 35 USC 101 as being drawn to patent-ineligible subject matter.
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 14-27 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. The use of comprising or consisting of claim language is clearly set forth in the MPEP as clear language. Clarification is required.
Claim 16, 18, 22 is indefinite over “the G- probe” because Claims 14 and 20 do not require a G-probe. The recitation lacks proper antecedent basis.
Claims 24-26 are rejected as indefinite over the recitation “the GAPDH-F, the GAPDH-R and the G-Probe” because Claim 20 and 22 lack proper antecedent basis. Claim 20 and 22 do not provide a G-probe or GAPDH primers.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
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 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.
Claims 14-15, are rejected under 35 U.S.C. 102(a)(1) as being anticipated by NEB catalog (1998/1999), pp. 121, 284.
The claims are directed to a reagent comprising two primers and probe “shown in” SEQ ID NO: 1, 2, and 3 and SEQ ID NO: 4-6. The use of comprising language provides additional probes and primers may be within the set. The claim contains additional language that set for the intended use of the kit. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art.
The NEB catalog offered for sale a random primer mix of 12mer and 24mer nucleotide primers. As the calculation below shows, about 3.2 x 108 molecules of every 12-mer and about 9 molecules of every single 24 mer are present in each tube of the 24 nucleotide mixtures.
a. Molecular weight of 12-mer:
12 x 325 daltons/nucleotide = 3,900 daltons = 3,900 g/mol
b. Total number of possible 12-mers:
412 = 1.6 x 107 molecules
c. How many molecules of 12-mer in a vial sold by NEB:
1 A260 unit = 33 µg = 3.3 x 10-5 g
3.3 x 10-5 g / 3,900 g/mol = 8.4 x 10-9 mol
(8.4 x 10-9 mol) x (6.02 x 1023 molecules/mol) = 5 x 1015 molecules
d. How many molecules of each 12-mer in a single vial:
5 x1015 molecules / 1.6 x 107 molecules = 3.2 x 108 molecules of each 12-mer per vial
e. Molecular weight of 24-mer:
24 x 325 daltons/nucleotide = 7,800 daltons = 7,800 g/mol
f. Total number of possible 24-mers:
424 = 2.8 x 1014 molecules
g. How many molecules of 24-mer in a vial sold by NEB:
1 A260 unit = 33 µg = 3.3 x 10-5 g
3.3 x 10-5 g / 7,800 g/mol = 4.2 x 10-9 mol
(4.2 x 10-9 mol) x (6.02 x 1023 molecules/mol) = 2.5 x 1015 molecules
h. How many molecules of each 24-mer in a single vial:
2.5 x1015 molecules / 2.8 x 1014 molecules = 9 molecules/vial
The claims encompass a large genus of possible nucleic acid primers with no particular base composition or length. The NEB catalog kits will inherently and necessarily contain 12 and 24 nucleotides primers encompassed by the claimed recitation.
Claim 14 requires a primer “shown in” SEQ ID NO: 1 and 2 and a probe “shown in” SEQ ID NO: 3. Here, the 12mer NEB primer kit inherently comprises fragments of SEQ ID NO: 1-3. Shown in encompasses fragments of SEQ ID NO: 1-3.
In the event the claims are amended to require primers and probe comprising SEQ ID NO: 1-3, the 24-mer primers meet these limitations. SEQ ID NO: 1 and 2 are 22 nucleotides in length and SEQ ID NO: 3 is 24 nucleotides. Therefore, the 24-mers comprise SEQ ID NO: 1-2 and consists of SEQ ID NO: 3. Claim 15 is similarly rejected.
Thus, the prior art inherently teaches each and every structural limitation of the instant claim.
Claims 14-15, are rejected under 35 U.S.C. 102(a)(1) as being anticipated Sarkar et al. (J. or Ethnopharmacology, Vol. 140, pages 443-446, 2012).
Sarkar teaches primers for the Human H1 mRNA and GAPDH (as an internal standard). With the assistance of Primer Express (Applied Biosystems, Foster City, CA, USA) the Human H1 mRNA sense primer (5′-CAGAGGATCAGATGTTAGGTGATAGC-3′), anti-sense primer (5′-AGCGGAGCCTCTTCCAAGTAA-3′) and probe (FAM-CTTCTCTCGACGGACTCAGATACCACC-TAMRA) were chosen.
The GAPDH primers were taught by Matsushita 2008. The primers were from Applied Biosystems.
Each of these sequences are “show in” the recited sequences. The language “shown in” encompasses fragments of the claimed sequences. This rejection would be overcome in the event that “shown in” is replaced with comprising or consisting of language.
Claim 14 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Meiler et al. (J. Exp. Med. Vol. 205, No. 12, pages 2887-2898, November 2008).
Meiler et al. teaches real time PCR of HR1. Meiler teaches the PCR primers and probes were designed based on sequence from GenBank including NM_001098213. The primers and probe are:
HR1 forward, 5′-TCTCGAACGGACTCAGATACCA-3′;
HR1 reverse, 5′-CCTGTGTTAGACCCACTCCTCAA-3′;
HR1 probe, FAM-ACAGAGACAGCACCAGGCAAAGGCAA-TAMRA;
The composition included using SYBR-PCR Master Mix and TaqMan RT reagents with random hexamers. The TaqMan RT kit comprises buffer, Taq enzymes, reverse transcriptase etc
Each of these sequences are “show in” the recited sequences. The language “shown in” encompasses fragments of the claimed sequences. This rejection would be overcome in the event that “shown in” is replaced with comprising or consisting of language.
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 14-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sarkar et al. (J. or Ethnopharmacology, Vol. 140, pages 443-446, 2012) in view of Meiler et al. (J. Exp. Med. Vol. 205, No. 12, pages 2887-2898, November 2008) and further in view of Rae et al. (Genbank Accession AF026261, January 7, 1998) and Untergasser et al. (Primer3Plus, an enhanced web interface to Primer3, Nucleic Acids Research, 2007, Vol. 35, 2007).
In the event the claims are amended to require the sequences comprise SEQ ID NO: 1-6, the following rejection is appropriate.
Sarkar teaches primers for the Human H1 mRNA and GAPDH (as an internal standard). With the assistance of Primer Express (Applied Biosystems, Foster City, CA, USA) the Human H1 mRNA sense primer (5′-CAGAGGATCAGATGTTAGGTGATAGC-3′), anti-sense primer (5′-AGCGGAGCCTCTTCCAAGTAA-3′) and probe (FAM-CTTCTCTCGACGGACTCAGATACCACC-TAMRA) were chosen.
Meiler et al. teaches real time PCR of HR1. Meiler teaches the PCR primers and probes were designed based on sequence from GenBank including NM_001098213. The primers and probe are:
HR1 forward, 5′-TCTCGAACGGACTCAGATACCA-3′;
HR1 reverse, 5′-CCTGTGTTAGACCCACTCCTCAA-3′;
HR1 probe, FAM-ACAGAGACAGCACCAGGCAAAGGCAA-TAMRA;
The composition included using SYBR-PCR Master Mix and TaqMan RT reagents with random hexamers. The TaqMan RT kit comprises buffer, Taq enzymes, reverse transcriptase etc (limitations of Claim 27).
Sarkar nor Meiler specifically teach the primers and probes comprising SEQ ID NO: 1-6 for HRH1 and GAPDH.
However, Rae teaches the histamine receptor H1 polynucleotide. Rae teaches a 1464 bp sequences that comprises SEQ ID NO: 1, 2, and 3 of the instant application.
SEQ ID NO: 1 is position 1067-1087; SEQ ID NO: 2 is 1131-1150 and SEQ ID NO: 3 is 1104-1124.
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. An alignment of primers 1, 2 and probe 3 are aligned to the sequence and aligned to Sarkar and Meiler. It is clear that the primers overlap the primers known in the art.
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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.”). Sarkar and Meiler teach the primers were designed with the assistance of primer express, a commercially available program for designing primers. Further, 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. 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 homologue of the above similar primers based on the known HRH1 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 Sarkar and Meiler to detect the same HRH1 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 HRH1 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 respect to Claim 16-19, the probes of Sarkar and Meiler each comprise FAM and TAMARA. It would have been prima facie obvious to have differentially labeled the probes to allow for differential detection.
Claims 20-27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sarkar et al. (J. or Ethnopharmacology, Vol. 140, pages 443-446, 2012) in view of Meiler et al. (J. Exp. Med. Vol. 205, No. 12, pages 2887-2898, November 2008) and further in view of Rae et al. (Genbank Accession AF026261, January 7, 1998) and Untergasser et al. (Primer3Plus, an enhanced web interface to Primer3, Nucleic Acids Research, 2007, Vol. 35, 2007) and further in view of Asuragen (WO 2016/138376, September 1, 2016).
Neither Sarkar, Meiler, Rae nor Untergasser teaches combining the claimed probes and primers into a kit comprising ROX, enzymes, PCR reaction solutions and standards.
However, Zeigler teaches a kits comprising primers, probes, ROX, standard core reagents, Taq, buffer mastermix, diluent (para 97).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention to have packaged primers, probes in kits with the necessary reagents to detect nucleic acids. The art is replete with kits comprising primers, probes, PCR reaction solutions, enzyme solutions, standards, ROX and nuclease-free water. The ordinary artisan would have been motivated to have added PCR solutions, enzyme solutions, ROX, standards in a kit with the HRH1 and GAPDH probes and primers to allow the ordinary artisan a convenient kit.
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.
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.
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 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 9, 2026
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