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 .
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on Apr. 6, 2026. Claims 1-21 are pending. Claims 19-21 are withdrawn. Claims 1-18 are currently examined.
Election/Restrictions
Applicant's election with traverse of Group I (Claims 1-18), directed to a method for quantifying a viral species, in the reply filed on April 6, 2026, is acknowledged. For the species election requirement, Applicant elects with traverse: (1) p24 capsid protein.
Applicant argues that it should be no undue burden on the Examiner to consider all the groups and species. Applicant' s argument is not persuasive. Although related, the inventive groups/species vary substantially that the searches are not coextensive and each distinct group/species requires its own search and considerations of other patentability issues as the art relating to one group/species would not provide the structural elements required for the other group/species. Thus, the search would be an undue burden on the Patent and Trademark Office resources due to the complex nature of the search in terms of computer time needed to perform the search and the subsequent analysis of the search results by the examiner.
For the reasons above, the Restriction is deemed to be proper, and is made Final. Accordingly, claims 19-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group.
Claims 1-18 are under examination on the merits.
Information Disclosure Statement
The Information Disclosure Statements (IDSs) submitted on 9/1/2023 and 12/13/2023 are in compliance with 37 CFR 1.97. Accordingly, the references listed in the IDSs are being considered by the examiner.
Claim Objections
Claim 1 is objected to because of the following informalities: claim 1 contains a typographical mistake on line 3, where it recites “virial” instead of “viral”. Appropriate correction is required.
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 1-18 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 1 recites “viral species” and “incubating a detectable dye with a viral species in presence of sodium dodecyl sulfate (SDS)”. The term “viral species” refers to more of a concept about the virus classification than the virus itself. Therefore, it is not clear what of the “ virus species” is incubated with the dye. Claims 2-17 depend on claim 1 but do not remedy this lack of clarity, and are thus also rejected.
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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.
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 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.
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 1 and 7-17 are rejected under 35 U.S.C. 103 as being unpatentable over Massie (Analysis by capillary electrophoresis with laser-induced fluorescence detection: from small molecules to whole cells. Dissertation. Wake Forest University. December 2010) in view of Craig (Electrophoresis 26, 2008-221, 2005).
The claimed invention is represented by claim 1, which encompasses a method for quantifying a viral species, the method comprising the steps of: preparing at least one labeled viral protein component by incubating a detectable dye with a viral species in the presence of sodium dodecyl sulfate (SDS); loading the labeled viral protein component onto a capillary electrophoresis (CE) capillary, wherein the CE capillary is filled with a buffer comprising a polymer matrix; applying a separation voltage to the CE capillary; detecting at least one labeled viral protein component with a detector, thereby producing a corresponding set of values; and quantifying a protein of interest in the viral protein component using the corresponding set of values (representative claim 1).
The Prior Art
Massie discloses that capillary electrophoresis (CE) is one of the most efficient separation techniques available for the analysis of large and small molecules, and instrumentation consists of a high voltage supply (typically about 30 kV), a fused silica capillary (typically 25-100 µm inner diameter) filled with buffer, two buffer reservoirs, two platinum electrodes, and a detector, which is typically located on-column so as to avoid efficiency losses associated with transfers to an external sample cell (Fig. 1, pp. 1-2, bridging para.). Massie teaches methods of capillary electrophoresis, and that since the separation in CE is based on the ratio of analyte size and charge, it is possible for viruses to be analyzed by CE because viruses have electrically charged capsids (p. 222, p. 241 printout). Additionally, Massie teaches that CE is a fast, inexpensive, specific and sensitive method for virus determination relative to other commonly used analytical techniques, with minimal risk of contamination and false positives, and reduced health risks to analysts when working with pathogenic viruses (p. 226, para. 2). Massie also discloses that capsid surface proteins are available for interactions with fluorescent dyes, and so derivatization of intact viruses may permit greater sensitivity and selectivity in their detection (p. 222, p. 241 printout).
Massie teaches a viable method to determine wild-type turnip yellow mosaic virus (TYMV) labeled with various fluorescent labels used for proteins, including fluorescamine, NN127, and Red-1c, which show great promise for studying other viruses without the need for time-consuming sample preparation or derivatization procedures (p. 222, p. 241 printout). The TYMV capsid is composed of 180 copies of a single coat protein (p. 225, p. 244 printout). Massie also discloses there are challenges when working with viruses in the context of CE, including their large size and aggregation, but that additives such as polyethylene glycol (PEG), polyethylene oxide (PEO), detergents, and methylcellulose in the CE running buffer can increase resolution and efficiency, reduce electroosmotic flow (EOF), and prevent aggregation or adsorption on the capillary wall (p. 226, p. 245 of printout).
Massie teaches that 10 kV separation voltage was a condition that lead to high efficiency peaks for virus samples (p. 229, col. 3, printout p. 248). Further, the instrumentation utilized electropherograms recorded using a BioRad Biofocus 2000 CE system with a 594 or 650 nm diode laser with 630 or 664 nm emission filter for Red-1c or NN127, respectively, or a 406 nm excitation wavelength for fluorescamine (p. 229, para. 3, printout p. 248; p. 230, printout p. 249). Massie also discloses that separation of complex or heterogenous samples containing viruses is a challenge in separations for mixtures, and that aggregation or macromolecular complexation among analytes may cause their co-migration (p. 234, p. 253 printout, para. 2). These complexes may exhibit increased interactions with the capillary wall when more complex, higher concentration mixture is analyzed, reducing resolution and separation efficiency (pp. 234-235, p. 253-255 printout, bridging para.). However, Massie contemplates that these effects might be reduced or eliminated by using buffer additives such as detergents (e.g., SDS) or polymers (e.g., polyethylene glycol; p. 235, p. 254 printout, para. 1).
Accordingly, Massie discloses a method for quantifying a viral species, preparing at least one labeled viral protein by incubating a detectable dye with a viral species, loading the labeled viral protein component onto a CE capillary filled with a buffer comprising a polymer matrix, applying a separation voltage the CE capillary, detecting at least one labeled viral protein component with a detector, thereby producing a corresponding set of values, and quantifying a protein of interest in the viral protein component using the corresponding set of values. Massie also discloses wherein the detectable dye is a fluorescent dye with an absorption wavelength and an emission wavelength of between about 480 nm and about 750 nm, the polymer matrix is polyethylene glycol, the detector is a fluorescence detector, and the method is used in a high throughput screening application or a rapid screening workflow. However, Massie does not specifically disclose preparing at least one labeled viral protein component by incubating a detectable dye with a viral species in the presence of SDS, as required by the instant invention.
Craig teaches that Py-1 and Py-6 are amino-reactive fluorescent reagents that consists of a pyrylium group attached to small aromatic moieties, and upon reaction with a primary amine there is a large spectral shift in the reagent, rendering them effectively fluorogenic (Abstract). Craig further discloses methods of labeling a test protein, human serum albumin, and analysis by capillary electrophoresis and laser-induced fluorescence detection (Abstract), wherein detection limits after a 60 min labeling reaction at 22°C (Py-1) and 50°C (Py-6) were 6.5 ng/ml for Py-1 and 1.2 ng/mL for Py-6, and that unlike many other amino reactive reagents used to label protein amino groups, reaction with Py-1 and Py-6 do not alter the charge of the protein and the advantage of this with respect to electrophoretic separations (Abstract). Craig also discloses that the Py-6 labeling reaction was prepared by combining 500 µL of 1.9-15 ng/mL HSA or 95-400 ng/mL of other proteins in 2.5 mM sodium tetraborate (pH unadjusted) containing 3.5 mM SDS, and 2 µL of 2.5 mM Py-6 stock solution for 60 min at 50°C (p. 2209, col. 2, para. 3).
It would have been obvious to one of ordinary skill in the art to modify the teachings of Massie to incorporate use of SDS in the labeling reaction. Regarding claim 1’s limitation preparing at least one labeled viral protein component by incubating a detectable dye with a viral species in the presence of SDS, Craig discloses Py-6 labeling reaction where protein sample containing 3.5 mM SDS is combined with Py-6 stock solution. Regarding claims 7 and 8’s limitations of the viral species being incubated at a temperature between about 40 °C to about 90°C and for at least 2 minutes, Craig discloses a Py-6 labeling reaction for 60 min at 50°C. Regarding claims 11 and 12’s limitations that the detectable dye is a pyrylium-based dye and more specifically an amine-reactive pyrylium dye, Craig discloses that Py-6 is an amino-reactive fluorescent reagent that consists of a pyrylium group attached to small aromatic moiety. Regarding claims 15-16 requiring the limit of quantification is in a low ng/ml range or in a sub ng/ml range, Craig discloses limits of detection in the ng/ml range, including 1.2 ng/mL for Py-6. Notably, the specification states “the term ‘sub ng/mL range’ includes amounts from about 0.01 ng/ml to about 49.99 ng/mL” (para. [032]). One of ordinary skill in the art would have been motivated to detect TYMV or other viruses in a specific, high-throughput, and rapid method. Massie discloses use of other fluorescent labels for similar CE methods. There would be a reasonable expectation of success because Massie and Craig demonstrate the suitability of the methods and reagents for labeling and quantifying protein species, including viruses. Therefore, claims 1 and 7-17 were prima facie obvious before the priority date of the instant invention.
Claims 2-6 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Massie and Craig (supra) as applied to claims 1 and 7-17 above, and further in view of Gutierrez-Granados, et al. (J Virol Methods. 2013 Oct;193(1):85-95. doi: 10.1016/j.jviromet.2013.05.010. Epub 2013 May 24. PMID: 23707924).
The claimed invention is represented by claim 6, wherein the viral species is a lentivirus, and the viral protein component is a structural protein, or more specifically p24 capsid protein.
The Prior Art
The teachings of Massie and Craig are described above. However, they do not teach a method for quantifying a viral species that is a lentivirus, or wherein the viral protein component is a capsid protein p24.
Gutierrez-Granados teaches that Gag polyprotein of HIV-1 assembles spontaneously in the vicinity of the plasmid membrane, giving rise to enveloped virus-like particles (VLPs), which offer great promise as HIV-1 vaccines (Abstract). Gutierrez-Granados also discloses that, robust VLP production and purification processes are required to generate VLPs of sufficient quality and quantity for pre-clinical and clinical evaluation, and simple, fast, and reliable quantitation tools are critical to develop, optimize, and monitor such processes (Abstract). Gutierrez-Granados further teaches that enzyme-linked immunosorbent assays (ELISA) have been used to quantify p24 antigen concentrations, which reflect virus particle concentrations (Abstract). Gutierrez-Granados also discloses that after pudding, immature HIV virions undergo a maturation process during which Gag is cleaved into its four domains: matrix (p17), capsid (p24), nucleocapsid (p7) and linker (p6), which leads to the formation of mature HIV particles (p. 86, col. 1, paras. 1-2).
It would have been obvious to one of ordinary skill in the art to modify the CE methods rendered obvious by Massie and Craig to measure lentiviral p24 of HIV-1 particles. Gutierrez-Granados discloses that p24 ELISA reflects viral particle concentrations and can be used to quantify p24 antigen concentrations. One of ordinary skill in the art would have been motivated to measure HIV particle or VLP concentrations to develop, optimize, and monitor HIV particle and VLP production and purification processes, as disclosed by Gutierrez-Granados. Regarding claims 2-3, HIV is a retrovirus and lentivirus. Regarding claims 4-6, Gutierrez-Granados discloses assays to detect and quantify HIV p24, which is a capsid protein (and thus also a structural protein). Regarding claim 18’s requirement that at least two labeled viral protein components are prepared, that would be inherent to labeling HIV VLPs or virions, because the HIV virion and VLP comprise a number of proteins, including matrix (p17), capsid (p24), nucleocapsid (p7) and linker (p6), as taught by Gutierrez-Granados. There would be a reasonable expectation of success because Massie discloses that capillary electrophoresis methods are suitable for measuring labeled viral proteins from virions, and Gutierrez-Granados discloses immunoassays to detect HIV p24 antigen. Therefore, claims 2-6 and 18 were prima facie obvious before the priority date of the instant invention.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 7, 20, 26, 52, 54, 55, 63, and 79 of copending Application No. 18/876,307 (PGPub US 20250377334 A1) in view of Massie (Analysis by capillary electrophoresis with laser-induced fluorescence detection: from small molecules to whole cells. Dissertation. Wake Forest University. December 2010), Craig (Electrophoresis 26, 2008-221, 2005), and Gutierrez-Granados, et al. (J Virol Methods. 2013 Oct;193(1):85-95. doi: 10.1016/j.jviromet.2013.05.010. Epub 2013 May 24. PMID: 23707924).
Each set of claims encompasses methods of capillary electrophoresis to evaluate or quantify viral species. While the instant claims are generic with regard to the viral species or drawn to retroviruses or lentiviruses, the copending claims are specific to adeno-associated virus (AAV). Each set of claims encompass specific polymer matrices (instant claims 1 and 13, ‘307 claims 1, 26, and 79). The copending claims also encompass the AAV sample being denatured using SDS and heated to a temperature of at least about 50°C for at least about 50 minutes (‘307, claims 54-55), the fluorescent dye is incubated with the denatured portion of the AAV sample at a temperature between about 40 °C and 90 °C for at least about 5 minutes (‘307, claim 63), and the fluorescent dye is a pyrylium-based dye (‘307, claim 63). Each set of claims also encompasses the detector being a fluorescence detector (instant claim 14, ‘307 claim 26). However, the copending claims do not disclose the viral species is a retrovirus, lentivirus, p24 capsid protein, specifically that the detectable dye has an absorption wavelength and an emission wavelength of between about 480 nm and about 750 nm, the limit of quantification being in a low or sub ng/ml range, or the method is used in a high-throughput screening application or a rapid screening workflow.
Notably, the teachings of Massie, Craig, and Gutierrez-Granados, and how they render obvious the instant claims and limitations thereof are specifically described above in the rejections under 35 U.S.C. §103.
The claimed invention would have been obvious to one of ordinary skill in the art in view of ‘307, Massie, Craig, and Gutierrez-Granados, because ‘307 and Massie disclose methods of using capillary electrophoresis to evaluate or quantify viral capsids, Craig discloses use of pyrylium-based fluorescent labels to evaluate proteins by CE, and Gutierrez-Granados discloses immunoassays for detecting and quantifying HIV p24. One of ordinary skill in the art would have been motivated to detect HIV infection or quantify HIV species, as Gutierrez-Granados discloses that p24 is an HIV capsid protein and p24 ELISA reflects virus particle concentrations. There would have been a reasonable expectation of success because CE methods for quantifying viral species using similar workflows and components are disclosed by the copending claims and prior art, as discussed above.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEFFREY MARK SIFFORD whose telephone number is 571-272-7289. The examiner can normally be reached 8:30 a.m. - 5:30 p.m. ET with alternating Fridays off.
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/JEFFREY MARK SIFFORD/Examiner, Art Unit 1671
/NIANXIANG ZOU/Primary Examiner, Art Unit 1671
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