DETAILED ACTION
Status of the Claims
Claims 1-4, 6-19, and 32-34 are currently pending and examined herein.
The following Office Action is in response to Applicant’s communication dated 12/22/2025. Rejection(s) and/or objection(s) not reiterated from previous office actions are hereby withdrawn. Applicant’s arguments with respect to claims 1-4, 7-19, and 34 as being rejected under 35 U.S.C. 103 over Spooner have been considered but are moot because the current ground of rejection does not rely on the Spooner reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument. The following rejection(s) and/or objection(s) are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
New Claim Rejections - 35 USC § 112(b)
Necessitated by Amendment
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 2-4, 7-11, and 13-14 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth 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.
Claims 2-4 and 7-9 each recites the limitation "the dried biological fluid sample". There is insufficient antecedent basis for this limitation in the claims at least because claim 1 recites two dried biological fluid samples.
Claims 7-11 and 13-14 each recites the limitation "the microsampling device". There is insufficient antecedent basis for this limitation in the claims at least because claim 1 recites two microsampling devices.
New Claim Rejections - 35 USC § 112(d)
Necessitated by Amendment
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 6 and 13 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
In the present case, instant claim 6 does not further limit claim 1, from which it depends, at least because it merely recites the same limitations for the lysis buffer as claim 1.
Claim 13 recites that “no more than 400 ng of genomic DNA is eluted from the absorbent tip of the microsampling device”, however, this limitation is already present in claim 1, from which the claim depends.
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.
Modified Claim Rejections – 35 U.S.C. 103(a)
Necessitated by Amendment
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.
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.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Bhattacharjee et al., Rudge et al., and Qiagen
Claims 1-4, 6-19, and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Bhattacharjee et al. (U.S. PGPub 2016/0281166 A1, cited in IDS of 09/12/2022, of record) in view of Rudge et al. (U.S. PGPub 2013/0116597 A1, cited in IDS of 09/12/2022, of record) further in view of Qiagen (Genomic DNA Handbook, June 2015, cited in IDS of 09/12/2022, of record).
Regarding claims 1-3, 6, and 17, Bhattacharjee discloses “methods and systems [that] can be used for detecting, predicting, screening and/or determining the presence, absence or predisposition of a genetic condition in a subject” as per [0078], including determining the presence or absence of gene mutations in hereditary cancer-related genes (e.g., in cancer as per [0080], with specific genes listed in the Tables) in a dried biological fluid sample from a subject (e.g., as per [0012]-[0015]) comprising:
(a) providing a dried blood sample from a subject (e.g., as per [0012]-[0015], which “can be obtained by a needle prick … from the arm, the foot, the finger, or the heel of the subject” as per [0095]);
(b) extracting genomic DNA from the dried blood sample (e.g. isolating DNA from dried blood samples as per [0012]-[0015] including with the use of lysis buffer comprising Proteinase K as per [0107] and/or [0256]);
(c) generating a library comprising amplicons corresponding to a plurality of hereditary cancer-related genes comprising APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A (p14ARF and p16), CHEK2, EPCAM, MEN1, MLH1, MSH2, MSH6, MUTYH, NBN, NF1, PALB2, PMS2, POLD1, POLE, PTEN, RAD51C, RAD51D, RET, SDHB, SDHC, SDHD, SMAD4, STK11, TP53, and VHL (e.g., Bhattacharjee discloses in several places including [0107]-[0114] and the Examples the use of whole genome amplification/sequencing and/or whole exome sequencing, which would reasonably amplify all genes, including those listed here),
wherein an index adapter sequence is ligated to at least one end of each amplicon in the library of amplicons (e.g., an adapter is ligated for next-generation sequencing as per [0070], [0149], and/or [0175]); and
(d) detecting the presence or absence of at least one mutation in at least one of the amplicons using high throughput massive parallel sequencing (e.g. as per [0028] and [0143]-[0157]).
Regarding the newly added limitations of “eluting at least two dried biological fluid samples” from “at least two absorbent tips of microsampling devices”, it is noted that Bhattacharjee discloses measuring samples from multiple subjects (e.g., as per the Title and/or para 0004, 0061-0066, 0069-0070, etc.), which would reasonably be collected in multiple samples. Similarly, Rudge discloses the use of multiple microsampling devices (e.g., several of the figures and/or para 0019-0022, 0072, etc.), also reasonably for use in collecting multiple samples.
However, it is noted that Bhattacharjee is silent on the limitation of using a dried blood sample eluted from an absorbent tip of a volumetric absorptive microsampling device, as set forth in claims 1 and 10.
Rudge teaches the use of absorbent tips (termed “absorbent probes” by Rudge) as the microsampling device (e.g. as per the Abstract and [0010], [0013], [0016], and Rudge claim 1).
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date of the application to use the absorbent tips as per Rudge in the screening method of Bhattacharjee in place of dried blood sample cards. One of ordinary skill in the art would have been motivated to do so since Rudge teaches that using such a tip would be “an improved method and apparatus for use in blood sampling that reduces or eliminates one or more … errors and difficulties” that includes those associated with dried blood spots on cards, as are used by Bhattacharjee, and specifically would avoid the “risk for collection of too much blood on the card” as per para 0005 and would be amenable to automation, specifically noting that “the blood spots are placed on rectangular cards which are difficult to manipulate by automated equipment, thus requiring extensive, expensive and time consuming manual handling and processing” as per para 0008. Note that the absorbent tips of Rudge collecting 20 µL of blood (see above) falls within the volume in which Bhattacharjee is interested in collecting (e.g. as per [0103]).
One of ordinary skill in the art at the effective filing date would have had a reasonable expectation of success in practicing the invention as claimed, since it would merely require the substitution of a microsampling device with an absorbent tip as per Rudge for the dried blood spot samples as per Bhattacharjee, wherein Rudge explicitly teaches that their microsampling devices with absorbent tips “is suitable as a quantitative sampling tool for biological fluids, preferably blood” (e.g. as per para 0010).
Bhattacharjee in view of Rudge is relied upon as above, however, it is noted that while Bhattacharjee teaches a lysis buffer with Tris·Cl, EDTA, and non-ionic detergents (e.g. as per para 0107, 0114, and 0258), it is silent on guanidine hydrochloride, polyoxyethylene (20) sorbitan monolaurate (e.g., Tween® 20), and octylphenol ethoxylate (e.g., Triton® X-100), as set forth in claim 6.
Qiagen teaches lysis buffer G2 comprising Tris·EDTA, guanidine hydrochloride, polyoxyethylene (20) sorbitan monolaurate (e.g., Tween® 20), and octylphenol ethoxylate (e.g., Triton® X-100) (e.g. as per page 63), to be used with lysing cells in blood with Proteinase K (e.g. as per pages 22-24).
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date of the application to perform the genetic screening as per Bhattacharjee in view of Rudge using the lysis buffer as per Qiagen. One of ordinary skill in the art would have been motivated to do so since Qiagen’s lysis buffer is a commercially available buffer system designed to work with Proteinase K for lysing blood samples prior to genomic DNA extraction and purification (e.g. their kits “provide an easy, safe, and reliable method for the isolation of pure high-molecular-weight genomic DNA” as per Qiagen page 7) and Bhattacharjee teaches at para 0107 that their methods “can use different lysis buffer compositions”.
One of ordinary skill in the art at the effective filing date would have had a reasonable expectation of success in practicing the invention as claimed, since the lysis buffer from Qiagen is commercially available and marketed to such bioscience researchers (e.g., graduate student, post-doc, etc.).
Regarding claims 4 and 11, Rudge discloses collecting blood from finger pricks (e.g. as per Fig. 2) at volumes of 20 µL (e.g. as per the Abstract and [0010], [0013], [0016], and Rudge claim 1).
Regarding claims 7-9, Bhattacharjee teaches the above, wherein the elution is performed in lysis buffer and Proteinase K for up to 15 minutes at 90ºC, up to 1 hour at 56ºC, or up to 16-18 hours at 56ºC, noting that the reference in para 0107 teaches a wide range of temperatures and times and in accordance with MPEP 2144.05(I), in the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists.
Regarding claims 12 and 34, Bhattacharjee teaches the above, wherein the hereditary cancer is breast cancer, ovarian cancer, colon cancer, or skin cancer (e.g. breast cancer as per para 0080).
Regarding claims 13-14, Bhattacharjee teaches the above, wherein about 100 ng to about 400 ng of genomic DNA is eluted (e.g. as per para 0012-0015).
Regarding claims 15-16, Bhattacharjee teaches the above, wherein the high throughput massive parallel sequencing is performed using pyrosequencing, reversible dye-terminator sequencing, SOLiD sequencing, Ion semiconductor sequencing, Helioscope single molecule sequencing, sequencing by synthesis, sequencing by ligation, or SMRTTM sequencing and wherein the high throughput massive parallel sequencing involves a read depth approach (e.g. HiSeq 2500 as per para 0175 or SOLiD as per 0149).
Regarding claims 18-19, Bhattacharjee teaches the above, wherein the plurality of amplicons is enriched using a bait set (e.g., capture probes as per [0032] and the Examples).
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Response to Arguments
The 12/22/2025 remarks argue: not all elements are taught and no motivation to combine references.
Applicant's arguments have been fully considered but they are not persuasive for at least the following reasons.
As an initial matter, Applicant’s arguments with respect to rejections under 35 U.S.C. 103 over Spooner have been considered but are moot because the current ground of rejection does not rely on the Spooner reference.
RE: “There is no reason to ‘fix’ Bhattacharjee's DBS cards with Spooner's tips because Bhattacharjee does not suffer from the specific quantitative defect Spooner aims to solve.”
In response, it is respectfully noted that as detailed in the rejection above, Rudge teaches that using their microsampling devices would be “an improved method and apparatus for use in blood sampling that reduces or eliminates one or more … errors and difficulties” that includes those associated with dried blood spots on cards, as are used by Bhattacharjee, and specifically would avoid the “risk for collection of too much blood on the card” as per para 0005 and would be amenable to automation, specifically noting that “the blood spots are placed on rectangular cards which are difficult to manipulate by automated equipment, thus requiring extensive, expensive and time consuming manual handling and processing” as per para 0008.
RE: “Even if a person of skill in the art were motivated to combine the references, the claimed invention achieves unexpected results that are not predicted by the cited references” and “It is unexpected that one could obtain high-quality NGS libraries for a 34-gene panel from such a restricted sample volume using the claimed lysis buffer. The "logical" expectation would be that the tiny volume of the VAMS tips (designed for drug small molecules) would yield insufficient DNA for multiplexed sequencing compared to the larger DBS cards. The success of the Applicants' specific protocol is a technical achievement that provides a non-obvious improvement over the cited references.”
As per MPEP § 716.01(c), allegations of unexpected results must be factually supported, such as by an appropriate affidavit or declaration to be of probative value. Arguments presented by the Applicant cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Further, as per MPEP § 716.02, it is the burden of applicant to establish that their results are indeed unexpected and significant, to compare the claimed invention with the closest prior art, and to show that objective evidence of nonobviousness is commensurate in scope with the claims. In the present case, the absorbent tips of Rudge collecting 20 µL of blood (e.g., as per para 0013-0016 of Rudge) falls within the volume in which Bhattacharjee is interested in collecting (e.g. as per [0103] of Bhattacharjee) and therefore there is reason to believe that such volume would be sufficient for DNA extraction, amplification, and sequencing, absent evidence to the contrary.
Bhattacharjee et al., Rudge et al., Qiagen, and Eiermann et al.
Claims 1-4, 6-19, and 32-34 are rejected under 35 U.S.C. 103 as being unpatentable over Bhattacharjee et al. (U.S. PGPub 2016/0281166 A1, cited in IDS of 09/12/2022, of record) in view of Rudge et al. (U.S. PGPub 2013/0116597 A1, cited in IDS of 09/12/2022, of record) and Qiagen (Genomic DNA Handbook, June 2015, cited in IDS of 09/12/2022, of record) further in view of Eiermann et al. (Annals of Oncology 12 (Suppl. I): S57-S62, 2001, cited in IDS of 09/12/2022, of record).
Bhattacharjee in view of Rudge and Qiagen is relied upon as above, however, it is noted that the reference is silent on the specific anti-cancer treatment, as set forth in claims 32-33.
Eiermann teaches the use of combinations of chemotherapy drugs, including trastuzumab (Herceptin®) and paclitaxel in the treatment of HER2 positive breast cancer (e.g. Abstract).
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date of the application to treat a patient identified with HER2 negative breast cancer as per Bhattacharjee in view of Rudge using trastuzumab and paclitaxel as per Eiermann. One of ordinary skill in the art would have been motivated to do so since Eiermann teaches that “the addition of trastuzumab to chemotherapy as first-line treatment significantly improves the survival of HER2-positive metastatic breast cancer patients to a clinically meaningful degree. Initial use of trastuzumab as part of combination therapy resulted in a decrease in relative risk of death by approximately 25% at 29 months of follow-up. In addition to this survival benefit, trastuzumab significantly increased TTP, response rate and duration, and TTF. Of particular note is that addition of trastuzumab to paclitaxel therapy more than doubled median TTP” as per the Discussion and conclusion section on page 61.
One of ordinary skill in the art at the effective filing date would have had a reasonable expectation of success in practicing the invention as claimed, since such drugs were commercially available and commonly used for cancer therapy, including breast cancer.
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Response to Arguments
Applicant does not offer further arguments regarding the above obviousness rejections beyond what was set forth with regard to the 35 U.S.C. § 103 rejection, above. To the extent that Applicant is merely repeating their previous argument, the Examiner contends that those issues were adequately addressed in the above sections, which are incorporated in their entireties herein by reference.
Conclusion
No claims are 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 extension fee 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 date of this final action.
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/JEREMY C FLINDERS/Primary Examiner, Art Unit 1684