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 June 24, 2026. Claims 1-8. 16-17, 26-27, 29, 36, 42-45, 52 and 58 are pending. Claims 4-8, 42-45, 52 and 58 are withdrawn. Claims 1-3, 16-17, 26-27, 29 and 36 are currently examined.
Election/Restrictions
Applicant's election without traverse of Group I (claims 1-3, 16-17, 26-27, 29 and 36), in the reply filed on June 24, 2026, is acknowledged.
Accordingly, claims 4-8. 42-45, 52 and 58 are withdrawn as being directed to a non-elected group.
Specification Objection
The use of trademarks has been noted in this application. The term “Capto” and ‘Proros” should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM, or ® following the term.
Although the use of trademarks is permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 27 is objected to because of the following informalities:
A period (.) between “surfactant. Selected” need to be removed.
Accordingly, 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 1-3, 16-17, 26-27, 29 and 36 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.
The base claim 1 recites a term “non-full rAAV particles” that renders the claims indefinite. It is unclear what the term “non-full rAAV particles” is represented for. The instant specification discloses that “non-full rAAV particles, as used herein, refer to a range of particles, or variants, including "empty" particles and "partial" particles. "Partial" particles herein refer to rAAV particles with some genetic material, but not complete genetic material as in full particles” (See [0008]). Based on the disclosure, it is still not clearly defined what the “non-full rAAV particles” is because the “partial particles” is a relative term without defining what the “partial” includes.
The base claim 1 also recites a term “exceeds” that renders the claims indefinite. The “exceeds” is a relative term that is lack of a measurable baseline and no clear boundary of how much of the full rAAV particles and non-full particles applied to the column is considered a “exceeds”.
Accordingly, one of ordinary skill in the art will not know the metes and bounds of the claims.
Claims 2-3 recite the term " preferably" renders the claims indefinite because it is unclear whether the limitations following the phrase are parts of the claimed invention.
Claim 3 contains the trademark/trade name “Poros 50 HQ, Poros 50 D, Poros 50 PI, Capto ImpRes Q, CIMmultusTM QA Monolithic Column and Poros XQ”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a column chromatography Medium and, accordingly, the identification/description is indefinite.
Claim Rejections - 35 USC § 112 (Scope of Enablement)
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, 16-17, 26-27, 29 and 36 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling to use anion exchange resin to separate full rAAV Particles and non-full Particles, does not reasonably provide enablement for a method for purifying/separating full recombinant adeno-associated virus (rAAV) particles using any chromatography medium as claimed.
The base claim 1 is directed to a method for purifying full recombinant adeno-associated virus (rAAV) particles comprising one of the limitations at the base claim 1 (b) for “loading the rAAV preparation in a loading buffer to a column comprising a chromatography medium, wherein the full rAAV particles have a higher binding affinity to the chromatography medium than the non-full particles, and the quantity of the full rAAV particles and non-full particles applied to the column exceeds the binding capacity of the chromatography medium, such that the non-full particles bound to the chromatography medium are displaced by the full rAAV particles into the flowthrough from the column”, where the “chromatography medium” is a generic medium/resin.
The instant specification discloses examples of separation of full rAAV particles and non-full particles. However, all the disclosed resins used in the examples are anion resins that includes Poros 50 HQ (See [0405]), Poros 50 D (See [0406]), Poros 50 PI (See [0407]), Capto ImpRes Q (See [0408]), and Poros XQ (See [0409]). Therefore, the specification does not provide evidence to support a method to purify/separate the full rAAV particles using any kind of chromatography medium. Thus, it does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wriqht, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).1
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:1) the nature of the invention, 2) the state of the prior art, 3) the breadth of the claims, 4) the amount of guidance in the specification, 5) the presence or absence of working examples, 6) the relative skill of those in the art, 7) the predictability or unpredictability of the art, and 8) and the quantity of experimentation necessary. Id. While it is not essential that every factor be examined in detail, those factors deemed most relevant should be considered.
M.P.E.P. §2164.03 [R-2] states: [I]n applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims. In re Soil, 97 F.2d 623,624, 38 USPQ 189, 191 (CCPA 1938). In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. In re Fisher, 427 F.2d 833,839, 166 USPQ 18, 24 (CCPA 1970). See also In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488,496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991). A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Therefore, the specification does not provide sufficient guidance to allow one skilled in the art to practice the claimed invention on the full scope with a reasonable expectation of success and without undue experimentation. In the absence of such guidance and evidence of working examples, the specification fails to provide an enabling disclosure commensurate in scope with the claim
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 1-3, 16, 26, 29 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Soltys et al. (WO2021158915A1, published on Aug. 12, 2021, International Filing Date: Feb. 05, 2021, hereinafter, “Soltys”).
The base claim 1 is directed to a method for purifying full recombinant adeno-associated virus (rAAV) particles comprising:
(a). providing an rAAV preparation comprising full rAAV particles and non-full rAAV particles;
(b). loading the rAAV preparation in a loading buffer to a column comprising a chromatography medium, wherein the full rAAV particles have a higher binding affinity to the chromatography medium than the non-full particles, and the quantity of the full rAAV particles and non-full particles applied to the column exceeds the binding capacity of the chromatography medium, such that the non- full particles bound to the chromatography medium are displaced by the full rAAV particles into the flowthrough from the column; and
(c). eluting the full rAAV particles bound to the chromatography medium with an elution buffer to obtain a purified preparation.
Soltys teaches a method for separating full recombinant adeno-associated vims (rAAV) particles from empty rAAV particles using anion exchange chromatography with an isocratic elution gradient of magnesium chloride (See Abstract).
Soltys teaches providing host cell lysate viral samples containing rAAV particle (See page 5, lines 21-28) such as those that have been transfected with AAV vector(s) (See page 25, lines 22-25; Example 7, page 35). Here it teaches the base claim 1 (a).
For the base claim 1 (b), Soltys teaches that the viral sample can be loaded on the anion exchange chromatography medium in the presence of a first isocratic buffer comprising Bis-Tris propane (See page 3, lines 15-20) and in certain embodiments, the methods further comprise loading the viral sample onto the anion exchange chromatography medium and washing the medium to remove the unbound fraction of the viral sample prior to elution (See page 4, lines 20-25). Although Soltys does not explicitly disclose the “exceeds the binding capacity of the chromatography medium”, it is reasonably considered that the “unbound fraction” can be partly caused by exceeding the binding capacity of the chromatography medium.
As for the “…the full rAAV particles have a higher binding affinity to the chromatography medium than the non-full particles…” claimed in the base claim 1 (b), Soltys teaches that given that the average pI of a full AAV particle is about 5.9 and the average pI of an empty AAV particle is about 6.3, the empty AA V particle will elute prior to the full AAV particle when using anion exchange chromatography because the loading buffer is at a pH above 6.3 to impart a negative charge onto the full and empty AAV particles, allowing them to bind to the positively charged anion exchange chromatography medium (See page 21, lines 12-32). Here the description teaches the full-AAV particle has a higher binding affinity to the chromatograph medium because the full capsids (with lower pI) are more negatively charged and have a stronger binding affinity than empty capsid.
As for the base claim 1 (C), Soltys teaches following the wash step, the bound fraction of the viral sample is eluted using either a linear or isocratic (i.e., step-wise) gradient comprising a salt (i.e., magnesium chloride). The negative ions in the salt solution compete with the bound molecules in binding to the resin and the point within the gradient at which a bound molecule is eluted from the anion exchange chromatography medium is based on the overall charge of the molecule. Given that the average pI of a full AAV particle is about 5.9 and the average pl of an empty AAV particle is about 6.3, the empty AAV particle will elute prior to the full AA V particle when using anion exchange chromatography (See page 21, lines 25-32).
Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Regarding claims 2 and 3, Soltys teaches that the anion exchange chromatography medium used in the presently disclosed methods comprises CIMmultus™ QA or CIM® QA as claimed.
Regarding claim 16, Soltys teaches that the loading step of anion exchange chromatography comprises adding the sample (e.g., viral sample), which can be prepared by dilution in an aqueous buffer (e.g., Bis-Tris propane) as claimed.
Regarding claim 26, Soltys teaches that the pH of the loading buffer should be at a pH above 6.3 (See page 21, lines 17-19).
Regarding claim 29, Soltys teaches that the methods rely on the use of an isocratic elution gradient of magnesium chloride as the sole salt to elute and separate the empty and full rAAV particles within a viral sample from an anion exchange chromatography medium (See page 2, lines 8-12).
Regarding claim 36, Soltys teaches that in some embodiments, the isocratic elution gradient comprises increasing the percentage of a second isocratic buffer to the first isocratic buffer, wherein the second isocratic buffer comprises Bis-Tris propane and magnesium chloride (See page 3, lines 16-19).
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Soltys as applied to claims 1-3, 16, 26, 29 and 36 above and in view of OH et al. (US 2021/0079422 A1, published on Mar. 18, 2021, PCT filed on Jun. 29, 2018) and Wang et al. (Mol Ther Methods Clin Dev. 2019 Sep 26;15:257-263).
Claim 17 requires the loading buffer comprises at least one salt of a cation selected from the group consisting of K(I), Li(I), Ca(II), Mg(II), Cu(II), Ba(II)), Co(II), Ni(II), Mn(II), Zn(II), Cd(II), Pb(II), Fe(III), Fe(II), Na(I), and NH4 +.
Soltys teaches the loading, and/or washing buffers comprise Bis-Tris propane (i.e., 1,3-bispropane). However, it is silent on comprising a salt as claimed.
OH describes a method of purification, production and manufacturing methods for recombinant rAAV vector particle, where the column chromatography steps include, for example, cation exchange chromatography, anion exchange chromatography, size exclusion chromatography and / or AAV affinity chromatography alone or in combination and in any order (See Abstract). OH teaches in Example 2 that a loading buffer contains a range of 10-50 mM Tris, pH 8.0-8.5, 100 mM NaCl (See e.g., [0214]), which teaches one of the salt as claimed. OH further teaches that additional salt to help recover AAV vector during or following filtration step in the Example 4 for describing an exemplary cell lysis and preparation prior to column purification.
Wang teaches that salts can potentially impact non-covalent interactions among capsids and interactions between AAV and column packing materials (See page 259, let column, paragraph 2) and discloses that including 2 mM MgCl2 in the sample dilution buffer prior to loading AAV1 resulted in the disappearance of the broad peaks and a dramatic increase in the intensity of the first two peaks (See page 258, right column, paragraph 4), which also teaches another salt as claimed.
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings from Soltys, OH and Wang to arrive at an invention as claimed. One of skill in the art would have been motivated to do so based on the benefit of different salt of a cation such as Mg (II) and Na (I) disclosed in OH and Wang’s studies. There would be a reasonable expectation of success to construct a method to include the proper salts into the loading buffer as claimed.
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Soltys as applied to claims 1-3, 16, 26, 29 and 36 above and in view of Moleirinho et al. (Curr Gene Ther. 2018;18(6):366-374) and Patricio et al. (Mol Ther Methods Clin Dev. 2019 Nov 20;17:99-106).
Claim 27 requires the loading buffer comprises at least one surfactant. selected from the group consisting of poloxamer 188, polysorbate 80, polysorbate 20, NP-40, Triton X-100, and Triton CG-110.
Soltys teaches the loading, and/or washing buffers comprise Bis-Tris propane (i.e., 1,3-bispropane). However, it is silent on the loading buffer contains at least one surfactant as claimed.
Moleirinho describes a clinical-grade oncolytic adenovirus purification using Polysorbate 20 as an alternative for cell lysis, and teaches that after the concentration step, 45 mL and 38 mL of viruses, from both Polysorbate 20 and Triton X-100 processes, were loaded into a strong anion exchange resin - Capto Q impRes (See page 370, right column, paragraph 2), which indicates that the loaded concentrated virus solution comprises the surfactant. Moleirinho also discloses that the surfactant can reduce protein aggregation and surface adsorption so that allows it to be widely used for therapeutic protein formulations, present in almost all licensed mAb, and their result shows that Polysorbate 20 has no negative effect on the steps of the process and, can increase the virus recoveries and removal of impurities formulation and the developed process is scalable and able to provide a highly purified product to be used in phase I and II clinical trials. (See page 367, left column, paragraphs 2-3; Abstract).
Patrício teaches that inclusion of PF68 surfactant improves stability of rAAV titer when passed through a surgical device used in retinal gene therapy and shows for the first time that both the biocompatibility and stability of rAAV2-REP1 are maintained following passage of the vector solution containing PF68 through the syringe loading used for human retinal gene therapy, where the claimed poloxamer 188 is the non-proprietary equivalent of PF68 (See Abstract and page 103, right column, paragraphs 2-3).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings from Soltys, Moleirinho and Patrício to arrive at an invention as claimed. One of skill in the art would have been motivated to do so to introduce the Polysorbate 20 or poloxamer 188 in the rAAV purification, for example, to apply the PF68 into the AAV purification buffers including the loading buffer to improve the stability od rAAV. There would be a reasonable expectation of success to develop such a method to add surfactant in the loading buffer as claimed.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RUIXUE WANG whose telephone number is (571)272-7960. The examiner can normally be reached Monday-Friday 8:00 am to 4:30 pm, EST.
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/RUIXUE WANG/ Examiner, Art Unit 1672
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