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 .
Election/Restrictions
Applicant’s election without traverse of Group I and species cHL, in the reply filed on March 5, 2026 is acknowledged.
Claims 8-10 and 13-16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim1. Election was made without traverse in the reply filed on March 5, 2026.
Information Disclosure Statement
The IDS received on September 15, 2023 and March 5, 2026 are proper and are being considered by the Examiner.
Drawings
New corrected drawings in compliance with 37 CFR 1.121(d) are required in this application because some of the figures are poor in quality and the figure texts therein are illegible. For example, figures 1, 15, 17, 18, and 19 contain texts that are poor in quality. Applicant is advised to employ the services of a competent patent draftsperson outside the Office, as the U.S. Patent and Trademark Office no longer prepares new drawings. The corrected drawings are required in reply to the Office action to avoid abandonment of the application. The requirement for corrected drawings will not be held in abeyance.
Nucleotide and/or Amino Acid Sequence Disclosures
The specification is objected for failing to comply with the Sequence Rules.
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c) (see page 11, which discloses reference sequence, read 1, read 2, and read 3 sequences, for example).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
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 2, 5, 23, and 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 2 is indefinite for the term, “6p23.3’ ” (emphasis added). It is unclear what is meant by the addition of a single-quotation mark. For the purpose of prosecution, the single quotation mark has been omitted.
Claim 5 is indefinite because it is unclear whether each oligonucleotide of the panel contains sequences that target the genetic alteration and UMIs, or the oligonucleotides containing UMIs are separate but part of the panel.
Claim 23 is indefinite because it is unclear whether the phrase, “panel comprises primers and/or probes” is intending to mean that the panel of oligonucleotides are to be used as primers and/or probes, or the panel further comprises primers and/or probes in addition to the oligonucleotides of the panel of parent claim 1.
Claim 27 is indefinite because the claim is fusing a method of using the panel of the oligonucleotides into a product claim.
The Federal Circuit decided an issue of first impression in that Court - whether a patent claim that covers both an apparatus and method of use of that apparatus passes muster under 35 USC §112, para. 2 (indefiniteness). Defending its "1-click system," Amazon won a summary judgment ruling of invalidity, IPXL Holdings, LLC v. Amazon.com, Inc., 333 F. Supp. 2d 513 (E.D. Va. 2004), which the Federal Circuit affirmed in part, 2005 U.S. App. LEXIS 25120.
After upholding the district court's claim constructions and affirming the finding that all but one of the asserted claims were anticipated, the Federal Circuit next affirmed the summary judgment of invalidity (for indefiniteness) for the remaining asserted claim, which read:
25. The system of claim 2 [including an input means] wherein the predicted transaction information comprises both a transaction type and transaction parameters associated with that transaction type, and the user uses the input means to either change the predicted transaction information or accept the displayed transaction type and transaction parameters.
Claim 25 on its face is directed to a "system." However, it also recites use steps ("the user uses the input means to ...change the predicted transaction information ... ") This claim was found indefinite by the district court.
Thus, for the above reasons, instant claim 27 is indefinite.
No further interpretation could be made for claim 27 for the purpose of prior art application.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 2, 4, 5, and 21-28 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a Written Description Rejection.
The written description requirement ensures that, “an applicant invented the subject matter which is claimed. Further, the written description requirement for a claimed genus may be satisfied through a sufficient description of a representative number of species by 1) reduction to practice; 2) reduction to drawing; or 3) disclosure of relevant identifying characteristics (i.e., structure of other physical and/or chemical properties, functional characteristics coupled with a known or disclosed correlation between function and structure) (MPEP 2163 at II(A)(3)(a)(ii)).
Reduction to Practice
The Federal Circuit reiterated that mere use of the same words in the specification and the claim (an in ipsis verbis test) is not sufficient to establish written description.
Presently, the claims presently embrace a collection (or a panel) of oligonucleotides that characterize a non-synonymous mutations from a list of genes that encode a corresponding protein, a structural variation in polynucleotide that encode a list of proteins, and copy number variation in a list of chromosomal loci, that embrace any such mutations and variations.
The application as filed appears to disclose a Table listing a list of oligonucleotide baits used to for identifying the variants, but the list is does not demonstrate a reasonable of number of such species so as to justify any copy number variations from a long list of chromosomal loci or mutations from the listed genes.
Reduction to Drawing
The specification disclose a subset of genes (Fig. 2A, 2B, 2C), but as discussed above, such is not a demonstration of possessing a reasonable number of species for the above-discussed genus embrace by the claims.
Disclosure of Relevant Identifying Characteristics
While one could argue that a skilled artisan would be able to identify the “representative number of species” of the remaining such mutations and variations for the recited genes and chromosomal loci, such intent would not satisfy the written description for the genus claims when, “the claims require an essential or critical feature which is not adequately described in the specification and which is not conventional in the art or known to one of ordinary skill in the art” (MPEP 2163(I)(A)). For the claims at issue, such essential or critical feature is the mutations and variants. Applicants have not disclosed enough number of species within the claimed genus.
As stated in University of California v. Eli Lilly and Co. at page 1404:
An adequate written description of a DNA ... "requires a precise definition, such as by structure, formula, chemical name, or physical properties," not a mere wish or plan for obtaining the claimed chemical invention. Fiers v. Revel, 984 F.2d 1164, 1171, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993). Accordingly, "an adequate written description of a DNA requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it; what is required is a description of the DNA itself." Id. at 1170, 25 USPQ2d at 1606.
Therefore, for the foregoing reasons, the genus embraced by the claims is not sufficiently described by the number of species disclosed in the specification, and therefore, the specification lacks written description of 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.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 2, 4, 5, and 21-27 are rejected under 35 U.S.C. 101 because the claimed invention is directed to the judicial exception of naturally occurring products without significantly more. The claims recite a collection of nucleotide base sequences which exist in portion in nature. This judicial exception is not integrated into a practical application because a nucleotide sequence that exists in nature, though claimed as a collection of multiple such sequences is nevertheless insufficient to add significantly more to the judicial exception.
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception based on the analysis under the current Patent Eligibility Guidelines (herein, “PEG”) as discussed below.
Step 1 Inquiry under PEG
Step 1 inquiry under Patent Eligibility Guidelines (herein, “PEG”) determines whether or not the claimed invention is drawn to one of the recognized statutory classes of invention. Claims 1-5 and 21-27 satisfy the present inquiry as being drawn to a product.
Step 2A Inquiry under PEG
A recently revised PEG now performs step 2A inquiry under a 2-prong analysis, and the subject claims analyzed accordingly as follows:
Prong 1:
Prong-1 inquiry under step 2A determines whether the claim(s) recites an abstract idea, a law of nature, or a natural phenomenon. As stated above, the panel of oligonucleotides are recited to embrace nucleotide sequences which are found in nature.
Therefore, claim recites a judicial exception.
Prong 2:
Prong-2 inquiry under step 2A determines whether or not the claims recite additional elements that integrate the judicial exception into a practical application in a manner that imposes a meaningful limit on the judicial exception.
Claim 1 recites the additional element in the form of the oligonucleotides in a collection, that is, in a panel. However, a collection of judicial exception does not render the collection patent eligible.
In Ambry, one of the patents under suit was U.S. Patent 5,747,282, with specific claims 16 and 17:
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Claims 16 and 17 of the ‘282 patent are drawn to a pair of primers (see reproduced claim 16):
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And upon consideration of these pair of primers, the court stated the below:
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Inferring from this, the functionality intended by recitation of the word, “collection” for “characterizing a genetic alteration” does not render the claimed subject matter patent-eligible, in much the same way the functionality of the primer pairs in Ambry decision did not render them patent-eligible.
This is because the primer pairs of the '282 patent (from Ambry) had their own specific functionality. They were single-stranded. They were in a pair, able to amplify a specific portion of the human genome (i.e., BRCA gene or a portion thereof).
While a pair of primers had not existed in their physically distinct forms (i.e., two separate single-stranded nucleic acids), which together performed a function of amplifying a specific portion of a human genome, the court found that the primer pairs did not satisfy the patent eligible requirement under 35 U.S.C.
Similarly, the claimed panel of oligonucleotides embrace nucleotide sequences that are found in nature, regardless of their intended usages and therefore, does not satisfy the eligibility requirement under 101 analysis.
Claims 2, 4, 21, 22, and 24-27 do not recite any additional feature than further describe the targets of the oligonucleotide panel, which also embraces sequences which are naturally occurring, and are subject to the same analysis as discussed above.
Claim 5 recites that the oligonucleotides comprise unique molecular UMIs. However, UMIs embrace those which exist in nature as endogenous UMIs, and therefore, continues to embrace a naturally existing sequence.
Claim 23 recites the additional feature in the form of primers and/or probe to the panel. However, primers and probes also embrace the same judicial exception issues as in Ambry discussed above, and therefore does not amount to patent eligibility.
As explained by the Supreme Court, in order to transform a judicial exception into a patent-eligible application, the additional element or combination of elements must do ‘more than simply stat[e] the [judicial exception] while adding the words ‘apply it’”. Alice Corp. v. CLS Bank, 573 U.S. __, 134 S. Ct. 2347, 2357, 110 USPQ2d 1976, 1982-83 (2014) (quoting Mayo Collaborative Servs. V. Prometheus Labs., Inc., 566 U.S. 66, 72, 101 USPQ2d 1961, 1965). Thus, for example, claims that amount to nothing more than an instruction to apply the abstract idea using a generic computer do not render an abstract idea eligible. Alice Corp., 134 S. Ct. at 2358, 110 USPQ2d at 1983. See also 134 S. Ct. at 2389, 110 USPQ2d at 1984 (warning against a § 101 analysis that turns on “the draftsman’s art”) (MPEP 2106.05(f))
Step 2B Inquiry under PEG
Step 2B inquiry of the PEG determines whether or not additional elements are provided and whether such elements amount to significantly more than the judicial exception in the claims.
Presently, the presently rejected claims do not recite additional features to amount to significantly more (as discussed above).
Therefore, the present claims lack patent eligibility.
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.
Claims 1, 2, and 21-25 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Liang et al. (The Oncologist, 2019, vol. 24, pages 219-228; IDS ref).
With regard to claims 1, 2, 22, and 25, Liang et al. teach a panel of oligonucleotides comprising one or more oligonucleotides that detection a mutation from B2M, XPO1, TNFAIP3, SOCS1:
“we performed a study using comprehensive genomic profiling (CGP) with a targeted NGS panel to test for gnomic aberrations in archival tumor samples from patients with HL [Hodgkins Lymphoma]” (page 220, 1st column)
“In order to identify common XPO1 mutations … we designed droplet digital polymerase chain reaction (ddPCR) probes against the E571K and E571V mutations … for the presence of XPO1 E571K or XPO1 E571V mutation” (page 220, 2nd column, 2nd paragraph)
“next most commonly mutated gene was B2M … with 12 mutations in 11 patients … next most frequent mutated gene was XPO1 … next most frequently mutated genes include TNFAIP3 … and SOCS1” (page 220, 2nd column bottom paragraph to page 221, 1st column, 1st paragraph)
With regard to claim 23, the ddPCR necessarily further comprises primers.
With regard to claim 24, Liang et al. teach that the B2M mutation may be associated with acquired resistance to PD-1 blockade in metastatic melanoma. Because the claim is directed to a product, absent evidence to the contrary, since the B2M mutation claimed in instant claim 1, this is assumed to characterize a feature of PD-1 sensitivity assessment.
With regard to claims 21 and 22, these oligonucleotides further describe one of the alternatives of the one or more oligonucleotides and are not actively required by the claims.
Therefore, Liang et al. anticipate the invention as claimed.
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.
Claims 5, 21, 22, 23, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Liang et al. (The Oncologist, 2019, vol. 24, pages 219-228; IDS ref) in view of Salk et al. (Nature Reviews, May 2018, vol. 19, pages 269-285).
The teachings of Liang et al. have already been discussed above.
In addition to the teachings of Liang et al. that have been discussed above, Liang et al. further teach a comprehensive genomic profiling of tumors from Hodgkin lymphoma patients, wherein the comprehensive profiling includes mutations in MSH6 (substitution mutation), JAK2 (copy number amplification) (see Table 1).
Liang et al. do not explicitly teach that oligonucleotides of length being about 50 to about 200 nucleotides or about 120 nucleotides are employed for these mutations (claim 21, 22, 23, and 26).
Liang et al. do not explicitly teach oligonucleotides comprising UMIs (claim 5).
Salk et al. teach that UMIs can be used for the purpose of improving accuracy of counting DNA or RNA molecules by eliminating biases from variable amplification as well as identifying sequencing errors from true mutations (see page 272, 1st paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Liang et al. and Salk et al., thereby arriving at the invention as claimed for the following reasons.
With regard to the combination of oligonucleotides that are designed to target the disclosed mutations of the panel, one of ordinary skill would have been motivated to do so for the purpose of simultaneously detecting them on an array, sequencing, or multiple PCR amplification for the well-known advantages provided by arrays and multiplex PCR assay, such as high-throughput and time-efficiency. Given that the mutation and the gene sequences have already been well-characterized, deriving a probe or primers for hybridizing (to), or sequencing the region of interest with primers and/or probes would have been well-within the purview of and routine to ordinarily skilled artisan by use of a plurality of commercially available primer/probe design programs. As well, one of ordinary skill in the art would have recognized that probes involved in detection in an array format can be tiled (Affymetrix array), or involve various lengths and therefore determining the length would have been within the purview of the artisan.
With regard to adoption of UMI into the primers, doing so would have been obvious in view of the well-established sequencing means that allows for the identification of the sequence reads and correcting for sequencing errors as discussed by Salk et al., yielding no more than a predictable outcome expected from a typical sequencing reaction.
In KSR, the Supreme Court particularly emphasized “the need for caution in granting a patent based on the combination of elements found in the prior art,” Id. at 415, 82 USPQ2d at 1395, and discussed circumstances in which a patent might be determined to be obvious. Importantly, the Supreme Court reaffirmed principles based on its precedent that “[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” Id. at 415-16, 82 USPQ2d at 1395. The Supreme Court stated that there are “[t]hree cases decided after Graham [that] illustrate this doctrine.” Id. at 416, 82 USPQ2d at 1395. (1) “In United States v. Adams, . . . [t]he Court recognized that when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.”
Therefore, the invention as claimed is deemed prima facie obvious over the cited references.
Claims 4 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Liang et al. (The Oncologist, 2019, vol. 24, pages 219-228; IDS ref) in view of Carbone et al. (Cancers, 2018, vol. 10, pages 1-7) and Li et al. (Journal of Virological Methods, 2006, vol. 133, pages 158-166).
The teachings of Liang et al. have already been discussed above.
While Liang et al. recognize that EBV are associated with HL, the artisans do not teach an oligonucleotide that hybridize to LMP1 of EBV.
Carbone et al. teach that treatment of HL with PD-1 targeting means differns on the EBV status the patient:
“Antibodies against PD-1 have shown clinical efficiency in patients affected by cHL …Expression of PD-L1 may be up-regulated by LMP-1 in lymphoblastoid B-cell lines through activation of JAK3 and STAT5 … EVB-related and EBV-unrelated cHL cases have a similar frequency of 9p24.1 gains/amplification … EBV-related cHL had higher PD-L1 expression according to a further up-regulation of PD-L1 by viral infection. According to these findings, treatments targeting PD-1 may successfully retore therapeutically immune responses against EVG-carrying HRS cell … characteristics of the tumour immune microenvironment in EBV-unrelated cHL would be distinct from EBV-related cHL, with specific implications for designing combination treatment regimens” (page 4, bottom paragraph to page 5, 1st paragraph)
Li et al. teach a method of detecting the presence of EBV (a gammaherpesvirus), wherein the artisans teach a probe that hybridizes to EBNA1 (see section 3.2, “DNA spots containing DNA encoding EBNA1 …”).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Liang et al. with the teachings of Carbone et al. and Li et al., thereby arriving at the invention as claimed for the following reasons.
The motivation to do so flows from the application of diagnosing Hodgkin’s lymphoma in a subject and the necessary decision to treat the subject. Because Li et al. teach that the EBV status of the disease is necessary for deciding treatment options in a subject with HL, one of ordinary skill in the art would have been motivated to combine the oligonucleotide probe that is specific to EBV with the probes specific for mutations found in HL, such as the probe employed by Li et al.
As to claim 28, the Office assumes that the probe employed by Li et al. is capable of annealing to the listed strains of EBV absent evidence to the contrary, and as an alternative would have been motivated to detect the presence of EBV from these known strains, as their sequence had been known with the same motivation to detect them in HL.
Therefore, the invention as claimed is deemed prima facie obvious over the cited references.
Conclusion
No claims are allowed.
Inquiries
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Young J. Kim whose telephone number is (571) 272-0785. The Examiner can best be reached from 7:30 a.m. to 4:00 p.m (M-F). The Examiner can also be reached via e-mail to Young.Kim@uspto.gov. However, the office cannot guarantee security through the e-mail system nor should official papers be transmitted through this route.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner's supervisor, Gary Benzion, can be reached at (571) 272-0782.
Papers related to this application may be submitted to Art Unit 1681 by facsimile transmission. The faxing of such papers must conform with the notice published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 CFR 1.6(d)). NOTE: If applicant does submit a paper by FAX, the original copy should be retained by applicant or applicant’s representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED, so as to avoid the processing of duplicate papers in the Office. All official documents must be sent to the Official Tech Center Fax number: (571) 273-8300. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (571) 272-1600.
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.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/YOUNG J KIM/Primary Examiner
Art Unit 1637 May 15, 2026
/YJK/
1 The Office also notes that some claims directed to non-elected inventions have been canceled. These inventions have also been withdrawn from consideration as being non-elected without traverse.
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