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 .
Applicant’s amendment submitted 1/16/2026 is acknowledged. Claims 12-13 and 31 are canceled.
Amended claims 1-11 and 14-30 are under examination on the merits.
Withdrawn Objections
Applicant’s arguments, see p. 1, filed 1/16/2026, with respect to the following rejections have been fully considered and are persuasive.
The following objections are hereby withdrawn due to Applicant’s amendment submitted on 1/16/2026:
Claim objections: claims 6 and 22 for minor informalities
Withdrawn Rejections
Applicant’s arguments, see pp. 1-2, filed 1/16/2026, with respect to the following rejections have been fully considered and are persuasive.
The following rejections are hereby withdrawn due to Applicant’s amendment submitted on 1/16/2026:
35 U.S.C. §112(b): claims 3-5, 9, 11, 16, 18, 20, and 28-30
35 U.S.C. §102: claims 1-2 and 19 under 35 U.S.C. 102(a)(1) as being anticipated by Young (Annu Rev Phys Chem. 2019 Jun 14;70:301-322. doi: 10.1146/annurev-physchem-050317-021247. Epub 2019 Apr 12. PMID: 3097829); claims 1 and 3-9 under 35 U.S.C. 102(a)(1) as being anticipated by Goldfain, et al. (J Phys Chem B. 2016 Jul 7;120(26):6130-8. doi: 10.1021/acs.jpcb.6b02153. Epub 2016 Apr 22. PMID: 27063451).
35 U.S.C. §103: claims 3, 7-8, and 14-16 under 35 U.S.C. 103 as being unpatentable over Young (supra) as applied to claims 1-2 and 19 above, and further in view of Kukura, et al. (WO 2018011591 A1, published 1/18/2018); claim 17 under 35 U.S.C. 103 as being unpatentable over Young and Kukura (supra) as applied to claims 1-3, 7-8, and 14-16 above, and further in view of Trenholm, et al. (US 20160122794A1, published 5/5/2016); claim 18 under 35 U.S.C. 103 as being unpatentable over Young (supra) as applied to claims 1-2 and 19 above, and further in view of R&D (Mass Photometry: revolutionary biotech by Refeyn Ltd. 11/20/2019, 1-page printout, retrieved 10/8/2025).
Maintained Rejections
Applicant's arguments filed 1/16/2026 have been fully considered but they are not persuasive regarding the following rejections, so those rejections are maintained:
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Previous Rejection Maintained and Claims added) Claims 1-3, 6-8, 14-16 and 18-21 are rejected under 35 U.S.C. 103 as being unpatentable over Young in view of Kukura (supra) and Pierson, et al. (Anal Chem. 2016 Jul 5;88(13):6718-25. doi: 10.1021/acs.analchem.6b00883. Epub 2016 Jun 16. PMID: 27310298; hereinafter referred to as “Pierson”). Claims 1-3, 7-8, 14-16, 18, and 19 are added, necessitated by amendment. Claim 18 is added because it was amended to require a mass photometer rather than a specific mass photometer, and Young discloses use of a mass photometer. Applicant’s new limitation of claim 20, that an amount of the preparation of viral particles is adjusted when a ratio of empty capsids to full capsids of between about 1:1 and about 2:1 is reached, is indefinite for the reasons described below. In the interest of compact prosecution, the examiner is interpreting it to mean between the ratio is 1:1 to 2:1, but that would be inherent to the claimed method.
(Previous Rejection Maintained) Claims 10-11 are rejected under 35 U.S.C. 103 as being unpatentable over Young, Kukura, and Pierson (supra) as applied to claims 1-3, 6-8, 14-16 and 18-21 above, and further in view of Drouin, et al. (WO2019210137A1, published 10/31/2019; hereinafter referred to as “Drouin”).
(Previous Rejection Maintained) Claims 22 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Young (supra) and further in view of Yin, et al. (Nat Rev Genet. 2014 Aug;15(8):541-55. doi: 10.1038/nrg3763. Epub 2014 Jul 15. PMID: 25022906). The rejection of claim 31 is hereby withdrawn due to cancellation of the claim.
(Previous Rejection Maintained) Claims 24-25 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Young and Yin (supra) as applied to claims 22 and 23 above, and further in view of Kukura (supra).
(Previous Rejection Maintained) Claim 26 is rejected under 35 U.S.C. 103 as being unpatentable over Young, Yin, and Kukura (supra) as applied to claims 22-25 and 28 above, and further in view of Trenholm, et al. (supra).
(Previous Rejection Maintained) Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Young and Yin (supra) as applied to claims 22 and 23 above, and further in view of R&D (Mass Photometry: revolutionary biotech by Refeyn Ltd. 11/20/2019, 1-page printout, retrieved 10/8/2025).
(Previous Rejection Maintained) Claims 29-30 are rejected under 35 U.S.C. 103 as being unpatentable over Young, Yin, and Kukura (supra) as applied to claims 22-25 and 28 above, and further in view of Goldfain (supra) and Smith, et al. (Methods Mol Biol. 2011;751:477-89. doi: 10.1007/978-1-61779-151-2_30. PMID: 21674350).
Applicant presents the following arguments
Methods of assessing kinetic behavior of bacteriophages are entirely different from the methods recited in Applicant’s claims pertaining to evaluation of viral vectors. Bacteriophages are much larger than any of the viral vectors recited in amended Claim 1. For example, the molecular weight of a bacteriophage is 25+ MDa while that of AAV is about 3-5 MD, and the seize of DNA contained in a bacteriophage (32 MDa) is far larger than the genome contained in a capsid of an AAV (~1 MDa). One of ordinary skill in the art would not have had any reasonable expectation of success in applying the methods of Young to viral vectors, such as those recited in Applicant’s claims, because Young does not provide one of ordinary skill in the art with any teaching or suggestion that the mass spectrometry methods described therein could be applied to and successful in assessing viral vectors such as those claimed.
Young also does not disclose using mass distribution data to determine levels of empty and full capsids in a preparation of viral vector particles, this determination is entirely unrelated to the assessment of the kinetics of DNA ejection from bacteriophages as disclosed in Young. Nowhere does Young disclose or suggest using either technique to differentiate levels of empty and full capsids of a viral vector, and it would not have been predictable that such methods could even be used for such a purpose in view of the size difference between the viral vectors as claimed and the bacteriophages of Young.
Young and Yin do not disclose or suggest a method of distinguishing non-viral gene therapy vectors. Young is directed to a method of assessing the kinetics of DNA ejection from macrophages, and does not provide any teaching or suggestion of implementing the imaging methods disclosed therein to assess a preparation of non-viral gene therapy vectors as claimed, nor would one of ordinary skill in the art have any reasonable expectation that the methods of Young could be successfully applied to non-viral gene therapy vectors in the manner set forth by Applicant. Young does not disclose or suggest using mass distribution data to determine levels of loaded and unloaded vectors, this determination is entirely unrelated to the assessment of the kinetics of DNA ejection from bacteriophages as disclosed by Young.
Yin does not supplement the aforementioned deficiencies, at best, Yin discloses that non-viral vectors may be used for gene therapy but does not provide any teaching or suggesting regarding methods for assessing the levels of loaded and unloaded vectors in a preparation thereof as claimed. The mere fact that non-viral vectors for gene therapy were known in the art would not have provided one of ordinary skill in the art with any teaching, motivation, or suggestion to arrive at Applicant’s amended claims.
Applicant’s arguments have been carefully considered but are not found to be persuasive because:
Applicant’s argument regarding the size of bacteriophage and the claimed viral vectors is not commensurate in scope with the claims. For example, herpes simplex virus has a relatively large viral genome exceeding 150,000 base pairs, whereas AAV genomes are only ~4.7 base pairs in length. Although AAV has a relatively small genome, there is no reason to think that there would not be a reasonable expectation of success in measuring it by ISCAMs. Mass spectrometry is extremely sensitive and capable of measuring very subtle changes in compositions, such as post-translational modifications, including acetylation, cysteinylation, carboxymethylation, and methylation, among modifications, of human BK virus structural proteins (see Fang, et al. Virology. 2010 Jun 20;402(1):164-76. doi: 10.1016/j.virol.2010.03.029. Epub 2010 Apr 9; Abstract).
Regarding Applicant’s argument about measuring ejection of DNA being entirely unrelated to determining levels of full vs empty particles, the only difference is semantics. Ejection of DNA from a viral particle results in empty particles. Further, as demonstrated by the reference Pierson, quantitative methods to assess full vs empty AAV capsids are known in the prior art.
Along those lines, one of ordinary skill in the art would have a reasonable expectation of success to utilize the methods for non-viral vectors. As disclosed by Young, interferometric scattering microscopy has been used to image lipids and their dis(assembly) dynamics, and Fang demonstrates that mass spectrometry is extremely sensitive and capable of measuring very subtle changes in compositions. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Where a rejection of a claim is based on two or more references, a reply that is limited to what a subset of the applied references teaches or fails to teach, or that fails to address the combined teaching of the applied references may be considered to be an argument that attacks the reference(s) individually. This is because "[T]he test for obviousness is what the combined teachings of the references would have suggested to [a PHOSITA]." In re Mouttet, 686 F.3d 1322, 1333, 103 USPQ2d 1219, 1226 (Fed. Cir. 2012). MPEP §2145(IV).
New Rejections Necessitated by Amendment
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.
(New Rejection Necessitated by Amendment) Claim 20 is 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.
The term “about” in claim 20 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The term “about” makes the metes and bounds of claim 20 unclear, because it is subjective and multiple practitioners can have varying opinions over how close a value must be to a second value to be “about” said second value and so it is not apparent what ratio(s) of empty to full capsids results in an amount of the preparation of viral particles being adjusted.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(New Rejection Necessitated by Amendment) Claims 4, 5, and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Young in view of Kukura and Pierson, et al. (supra), as applied to claims 1-3, 6-8, 14-16 and 18-21 above, and further in view of Goldfain, et al. (J Phys Chem B. 2016 Jul 7;120(26):6130-8. doi: 10.1021/acs.jpcb.6b02153. Epub 2016 Apr 22. PMID: 27063451) and Mietzsch, et al. (J Virol. 2014 Mar;88(5):2991-3003. doi: 10.1128/JVI.03371-13. Epub 2013 Dec 26. PMID: 24371066).
The Prior Art
The teachings of Young, Kukura, and Pierson were previously described. However, they do not teach a method wherein the glass surface is chemically modified or specifically derivatized with ligands capable of binding the viral particles, nor does it teach wherein said preparation comprises a salt.
Goldfain discloses use of interferometric scattering (or holographic microscopy) as a label-free imaging method (p. 6130, col. 2), wherein the position, orientation, and DNA content of bacteriophages in solution near a planar, functionalized glass surface is observed (Abstract; Fig. 2). Goldfain specifically discloses functionalizing the coverglass with APTES to produce an electrostatic attraction between the negatively charged phage and the positively charged APTES surface (p. 6134, col. 1, para. 1). Functionalization of the glass surface causes the phage to stick, enable measuring in-plane motion (p. 6131, col. 1, para. 2). Goldfain also discloses use of TNM buffer (50 mM Tris-HCl pH7.5, 100 mM NaCl, 8 mM MgCl2 (p. 6131, col. 1, para. 3). Additionally, Goldfain utilizes bacteriophage stocks diluted to 1012 plaque forming units per mL (p. 6131, col. 1, para. 3). Goldfain’s method allows for real-time observation of phage DNA ejection, as well as distinguishing between full and empty phage capsids (e.g., Fig. 5 A & D).
Accordingly, it would have been obvious to one of ordinary skill in the art to modify the method of Young, Kukura, and Pierson to utilize a chemically modified glass surface that is derivatized with ligands capable of binding the viral particles, and use of buffers comprising a salt, as disclosed by Goldfain to be suitable for interferometric microscopy of viral particles. Goldfain discloses functionalization of the glass surfaces causes the viral particle to stick, enabling measurement of in-plane motion. One of ordinary skill in the art would have been motivated to cause the viral particle to stick, enabling measurement of in-plane motion. There would have been a reasonable expectation of success because Goldfain demonstrates use of such components in methods involving other viruses. However, Goldfain does not disclose a specific AAV ligand known to bind AAV virions.
Mietzsch discloses that all currently identified primary receptors of adeno-associated virus (AAV) are glycans, and that depending on the serotype, these carbohydrates range from hepararan sulfate proteoglycans, glycans with terminal sialic acids, to galactose moieties (Abstract). Mietzsch also discloses glycan array screening, wherein different glycan structures are printed on microscope glass slides (p. 2992, col. 2, para. 4).
Accordingly, it would have been obvious to use the glycans disclosed by Mietzsch, which are demonstrated to bind particular AAV serotypes, as the ligands for the obvious method. Mietzsch demonstrates that particular glycans bind specific AAV, thus, a person having ordinary skill in the art would choose the glycans specific for a given AAV serotype of interest, which are disclosed by Mietzsch. One of ordinary skill in the art would have been motivated to causes the AAV to stick, enable measuring in-plane motion. There would have been a reasonable expectation of success because Goldfain demonstrates use of such components in methods involving other viruses, and Mietzsch discloses printing glycans on microscope glass (and thus that particular glycans are suitable ligands for AAV on microscope glass. Therefore, claims 1-9, 14-16 & 18-21 were prima facie obvious before the priority date of the instant invention.
(New Rejection Necessitated by Amendment) Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Young in view of Kukura and Pierson, et al. (supra), as applied to claims 1-3, 6-8, 14-16 and 18-21 above, and further in view of Trenholm, et al. (US 20160122794A1, published 5/5/2016).
The Prior Art
The teachings of Young, Kukura, and Pierson were previously described. However, they do not teach a method wherein the surface is a microfluidic channel or multiwell plate.
Trenholm discloses systems and methods for pathogen detection, which may comprise a microfluidic disk having a plurality of reaction chambers for combining a sample and amplification substances, and apparatuses for pathogen detection comprise a storage unit, a sensor unit, and a disposal unit (Abstract). Trenholm specifically discloses that the detector can take any form that is suitable for the detection of a desired substance, including interferometric scattering microscopy (iSCAT; para. [0072]). Additionally, Trenholm discloses that a samples may be exposed in microfluidic channels (para. [0076]).
It would have been obvious to one of ordinary skill in the art to modify the method of Young, Kukura, and Pierson to utilize the sample holding approaches taught by Trenholm, where a sample is held in a microfluidic disc or microfluidic channel. Trenholm discloses systems and methods for pathogen detection, which may comprise a microfluidic disk having a plurality of reaction chambers for combining a sample and amplification substances, and apparatuses for pathogen detection comprise a storage unit, a sensor unit, and a disposal unit (Abstract). Trenholm specifically discloses that the detector can take any form that is suitable for the detection of a desired substance, including interferometric scattering microscopy (iSCAT; para. [0072]). Additionally, Trenholm discloses that a samples may be exposed in microfluidic channels (para. [0076]).
One of ordinary skill in the art would have been motivated to use a microfluidic channel as a sample holder for holding a sample, as taught by Trenholm. There would be a reasonable expectation of success because Trenholm contemplates use of iSCAT as a detector approach for its methods. Therefore, claims 1-3, 6-8, 14-21 were prima facie obvious before the priority date of the instant invention.
Conclusion
No claim is 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 nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to 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
/Michael Allen/Supervisory Patent Examiner, Art Unit 1671
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