DETAILED ACTION
Disposition of Claims
Claims 1-2, 4, 8, 11, 13-15, 18, 25, 28, 33-38, 41, 43-44, and 46 were pending. Claims 1-12, 16-17, 19-24, 26-27, 29-32, 39-40, 42, 45, and 47-50 have been cancelled. Amendments to claims 13-15, 18, 25, 36-38, 41, 44 are acknowledged and entered. Claims 13-15, 18, 25, 28, 33-38, 41, 43-44, and 46 will be examined on their merits.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20230076072A1, Published 03/09/2023. Amendments to the specification presented on 12/24/2025 are acknowledged and entered.
Applicant is encouraged to utilize the new web-based Automated Interview Request (AIR) tool for submitting interview requests; more information can be found at https://www.uspto.gov/patent/laws-and-regulations/interview-practice.
Response to Arguments
Applicant's arguments filed 12/24/2025 regarding the previous Office action dated 06/26/2025 have been fully considered. If they have been found to be persuasive, the objection/rejection has been withdrawn below. Likewise, if a rejection/objection has not been recited, said rejection/objection has been withdrawn. If the arguments have not been found to be persuasive, or if there are arguments presented over art that has been utilized in withdrawn rejections but utilized in new rejections, the arguments will be addressed fully with the objection/rejection below.
Optional Authorization to Initiate Electronic Communications
The Applicant’s representative may wish to consider supplying a written authorization in response to this Office action to correspond with the Examiner via electronic mail (e-mail). This authorization is optional on the part of the Applicant’s representative, but it should be noted that the Examiner may not initiate nor respond to communications via electronic mail unless and until Applicant’s representative authorizes such communications in writing within the official record of the patent application. A sample authorization is available at MPEP § 502.03, part II. If Applicant’s representative chooses to provide this authorization, please ensure to include a valid e-mail address along with said authorization.
Drawings
(Objection withdrawn.) The objection to the drawings is withdrawn in light of the amended drawings submitted.
Specification
(Rejection withdrawn.) The rejection of the abstract of the disclosure is withdrawn in light of the amendments to the abstract.
Claim Rejections - 35 USC § 112(b); Second Paragraph
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection maintained in part and extended – necessitated by amendment.) Claims 13-15, 18, 25, 28, 33-38, 41, 43-44, and 46 thereof remain 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. Note the rejection of claims 1, 2, 4, 8 and 11 is withdrawn in light of the cancellation of said claims.
The term “about” in claim 13 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. As the claims have been amended to recite arbitrary ranges (e.g. “…about 20 mM histidine…” “…about 175 mM sodium chloride…” etc.), and the claims have been amended to recite functional language, it is unclear as to what “about” stands for and whether or not said unidentified range can still result in the claimed functional language (see 35 USC 112a rejection infra.)
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant claim 13 is rejected on the grounds of being indefinite. Claims 14-15, 18, 25, 28, 33-38, 41, 43-44, and 46 are also rejected since they depend from claim 13, but do not remedy these deficiencies of claim 13.
Response to Arguments
Applicant's arguments filed 12/24/2025 have been fully considered but they are not entirely persuasive.
With the amendments to the claim that now include functional language, and with the term “about” not being specifically defined in the specification, it remains unclear as to the exact metes and bounds of the composition now claimed that would arrive at the purported function. This is elaborated upon further in the written description rejection infra.
For at least these reasons, the claims remain rejected on the grounds of being indefinite.
(New rejection – necessitated by amendment.) Claim 13 and dependent claims 14-15, 18, 25, 28, 33-38, 41, 43-44, and 46 thereof 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 “maintains stability” in claim 13 is a relative term which renders the claim indefinite. The term “maintains stability” 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. It is unclear what would, and would not, be considered an “unstable” composition (e.g. loss of AAV vector integrity, pH change, particle aggregation, color change, etc.) It is unclear if a certain amount of gain/loss in any of these measurable parameters is acceptable or unacceptable (e.g. wherein “stability” is measured as a less than 5% increase or decrease in pH of solution, etc.). It is unclear from the claim and the guidance in the specification how one can measure or assess if the liquid is, or is not, “stable” after incubation for that duration of time at that specific temperature.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant claim 13 is rejected on the grounds of being indefinite. Claims 14-15, 18, 25, 28, 33-38, 41, 43-44, and 46 are also rejected since they depend from claim 13, but do not remedy these deficiencies of claim 13.
(Rejection withdrawn). The rejection of Claim 13 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to the claims.
(Rejection withdrawn). The rejection of Claim 36 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to the claims.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 13 is drawn to a liquid pharmaceutical composition comprising:
(a) an adeno-associated virus (AAV);
(b) about 20 mM histidine;
(c) about 3% (w/v%) trehalose;
(d) about 0.03% (w/v%) poloxamer 188; and
(e) about 175 mM sodium chloride;
wherein the pharmaceutical composition maintains stability for at least 12 months at 5o C.
Further limitations on the pharmaceutical composition of claim 13 are wherein the pH of the pharmaceutical composition is from about 6 to about 8 (claim 14); wherein the pH of the pharmaceutical composition is from about 6.3 to 8.3 (claim 15); comprising about 1e13 vg/mL to about 6e15 vg/mL of the AAV (claim 18); wherein the AAV is a recombinant AAV (rAAV) comprising an rAAV genome comprising a transgene (claim 25), wherein the transgene encodes a protein selected from the group consisting of glucose-6-phosphatase (G6Pase) and frataxin (FXN)(claim 28), wherein the rAAV genome further comprises a 5' inverted terminal repeat (5' ITR) nucleotide sequence 5' of the transgene, and a 3' inverted terminal repeat (3' ITR) nucleotide sequence 3' of the transgene (claim 33), wherein the 5' ITR nucleotide sequence is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence set forth in SEQ ID NO: 39, 41, or 42, and/or the 3' ITR nucleotide sequence is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the nucleotide sequence set forth in SEQ ID NO: 40, 43, or 44 (claim 34), wherein the rAAV comprises an AAV capsid comprising an AAV capsid protein (claim 35), and wherein the AAV capsid protein is from or derived from AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV13, AAV-DJ, AAV-LKO3, NP59, VOY101, VOY201, VOY701, VOY801, VOY1101, AAVPHP.N, AAVPHP.A, AAVPHP.B, PHP.B2, PHP.B3, G2A3, G2B4, G2B5, PHP.S, AAVRh32.33, AAVrh74, and AAVrh10 (claim 36).
Claim 37 is drawn to a method of transducing a target cell in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 13 under conditions whereby the target cell is transduced, namely in a human subject (claim 43).
Claim 38 is drawn to a method of expressing a transgene in a target cell in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 13 under conditions whereby the target cell is transduced and the transgene is expressed.
Claim 41 is drawn to a method of treating or preventing a disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 13.
Claim 44 is drawn to a method for the preparation of a pharmaceutical composition of claim 13, wherein the method comprises the steps of mixing components (a)-(e), wherein the method further comprises the step of storing the pharmaceutical composition at a temperature from about -800C to about 250C (claim 46).
Claim Rejections - 35 USC § 112(a); First Paragraph
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.
(New rejection – necessitated by amendment.) Claim 13 and dependent claims 14-15, 18, 25, 28, 33-38, 41, 43-44, and 46 thereof 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.
The following quotation from section 2163 of the Manual of Patent Examination Procedure is a brief discussion of what is required in a specification to satisfy the 35 U.S.C. 112 written description requirements for a generic claim covering several distinct inventions:
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice .... reduction to drawings .... or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus... See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
Thus, when a claim covers a genus of inventions, the specification must provide written description support for the entire scope of the genus. Support for a genus is generally found where the applicant has provided a number of examples sufficient so that one in the art would recognize from the specification the scope of what is being claimed.
Claims 13-15, 18, 25, 28, 33-38, 41, 43-44, and 46 are rejected as lacking adequate descriptive support for any liquid pharmaceutical composition which results in the function of “maintaining stability” for at least 12 months at 50C, and methods of using said compositions.
In support of the claimed genera (any liquid composition comprising any adeno-associated virus (AAV), the approximate amounts claimed of histidine, trehalose, poloxamer 188, and NaCl), the application discloses one example (Formulation 9) which comprises the exact amounts of histidine buffer, trehalose, poloxamer 188, and NaCl at a pH of 7.3 and an unknown AAV serotype at an unknown concentration and also appears to exhibit what Applicant defines as being a “stable formulation.” It appears that the AAV comprises Clade F capsid material (¶[0183]), but it is unclear if this means that only capsid protein was present (e.g. VP1, VP2, and/or VP3 from a clade F AAV) or if whole AAV virions from Clade F (e.g. AAV9 or any hematopoietic stem cell-derived AAV (AAVHSC)) were in the composition. It is unclear what the concentration of AAV components were in these formulations (Starting at ¶[0166]; Examples 1-5 of specification). Formulation 9 was noted to maintain the same vector genome numbers when incubated at room temperature (25 deg C) or approximate human body temperature (40 deg C)(¶[0172]; Fig. 3) over a period of 8 weeks, although it looks like in Fig. 3 that all the compositions comprised different starting concentrations of AAV, and even somehow experienced an increase in AAV concentration over time (Figure 3.) Only Formulation 9 was tested for “stability” by assessing vector genome titers, capsid titers, AAV vector aggregates, AAV vector purity, VP1 capsid protein integrity, and AAV vector potency (Fig. 12) over a period of 12 months. Said formulation was not compared to any other formulation. No other AAV serotypes or clades appear to have been tested. No other concentrations of the components claimed appeared to have been tested. Therefore, it is unclear if Formulation 9 only works at the exact concentration for the exact AAV Clade tested, or if said composition can have components present in a range of histidine, trehalose, poloxamer 188, and NaCl at any pH and maintain the stability. It is unclear as to what concentration of starting material of AAV is “stabilized” by this formulation. Thus, the application fails to provide sufficient examples of any species within the claimed genera.
Further, while the claims provide both a structure and a function, the application fails to draw any correlation between the two. In other words, there is no evidence that any AAV at any starting concentration in the claimed composition can maintain stability when stored at the claimed temperature for 12 months. Moreover, no correlation has been made as to which AAV clades, isolates, chimeras, or serotypes are stabilized by this solution, and the criticality of the parameters of each condition in the solution. It is unclear if the pH must be within a specific range, as the art has noted the pI (isoelectric point) of different AAV serotypes ranges due to the capsid makeup and whether or not said capsid is full, and said pI for AAV can generally range anywhere from 5.0 to 9.5 (Venkatakrishnan B, et. al. J Virol. 2013 May;87(9):4974-84.; see Fig. 4). Lastly, the specification does not establish if any additional components (e.g. mixture of AAV, additional reagents, excipients, fillers, stabilizers, etc.) are tolerated in the composition, as the claims are broadly drawn to compositions “comprising” the noted components, which allows the inclusion of additional, unrecited elements. It is unclear (see 35 USC 112b rejection supra) how one is to measure “stability” over time, if all the parameters tested must be measured and if all the parameters must be within a certain threshold. As AAV compositions for pharmaceutical use are often employed for gene therapy or vaccine purposes, said compositions must be empirically tested for long-term stability to ensure the safety, potency, and consistency of the gene therapy product. Because AAV vectors are complex biological structures (e.g. protein capsids containing DNA) that are susceptible to degradation, aggregation, and loss of activity, and because AAV vectors differ in their structural and physiological makeup, empirical data is required to define appropriate storage conditions and ensure the drug remains effective over its shelf life. Formulation development usually starts with identification of the pH associated with maximal stability and selection of a buffer with an adequate buffering capacity in the target pH range. Common advice for formulating proteins includes avoiding a pH close to the isoelectric point of a particular active ingredient and minimization of ionic strength. However, AAV formulations could require use of a higher ionic strength in order to prevent aggregation. The inhibition of AAV aggregation, especially in AAV compositions of higher concentration, by ionic excipients depends on their type and concentration, with multi-charged salts being effective at concentrations corresponding to 180–220 mOsm versus 300–320 mOsm for NaCl and amino acids. How the AAV is produced also affects the stability of said AAV, as removal of DNA impurities by treatment with nuclease reduces aggregation (Rodrigues GA, et. al. Pharm Res. 2018 Dec 27;36(2):29.) As the art has shown, a great many parameters need to be empirically optimized and tested for each unique AAV, and one composition that shows “stability” for one recombinant AAV may not necessarily be stabilizing for another AAV. The teachings of the art therefore fail to indicate that, without such evidence, those in the art would have expected the full scope of the claimed compositions to confer the claimed stability.
Thus, in view of the above, there would have been significant uncertainty as to which compositions would be able confer the claimed “stability” for which AAV types. In view of this uncertainty and the lack of sufficient examples of the claimed genera, the claims are rejected for lack of adequate written description support.
Claim Rejections - 35 USC § 102
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection withdrawn.) The rejection of Claims 1-2, 4, 8, 11, 14-15, 18, 25, 35-36, 41, 44, and 46 under 35 U.S.C. 102(a)(1) as being anticipated by Fiedler et. al. (US20190255126A1, Pub. 08/22/2019; hereafter “Fiedler”) as evidenced by Falkner et. al. (US20170233455A1, Pub. 08/17/2017; hereafter “Falkner) is withdrawn in light of the amendments to the claims.
(Rejection maintained in part and extended – necessitated by amendment.) Claims 13-15, 18, 25, 33, 35-38, 41, 43-44, and 46 remain rejected under 35 U.S.C. 102(a)(2) as being anticipated by Marshall et. al. (WO2020214929A1, Pub. 10/22/2020; hereafter “Marshall”.) Note the rejection of claims 1-2, 4, 8, 11, is withdrawn in light of the cancellation of said claims.
The Prior Art
Marshall teaches a stable pharmaceutical formulation comprising recombinant adeno-associated virus (rAAV) particles and a buffering agent, a sugar, and an amorphous salt (entire document; see abstract; reference claim 1; ¶[0009]). The buffering agent may be histidine buffer at a concentration of between about 1 mM and about 50 mM, or about 20 mM (¶[0110][0139]). Marshall teaches the formulation may comprise a non-reducing sugar such as trehalose, at a concentration between about 50 mM and about 400 mM, or about 150 mM or about 250 mM (¶[0017][0119][0192]; reference claims 29-35). Marshall teaches the non-ionic surfactant may be poloxamer 188, and may be present in a concentration ranging from about 0.0001% to about 0.5% (¶[0007][0135-0138]). Marshall teaches the composition may comprise a salt, such as NaCl, at concentrations ranging from 20 to 180 mM (¶[0135-0136][0138][0150][0165-0166][0169][0182-0183][0186]; Fig. 2).
Marshall teaches the formulation is a liquid formulation, or a reconstituted formulation from a lyophilized formulation (¶[0010][48.][0133] preceding and including Sect. 4.1 “Illustrative Embodiments 4.1.1. Set 1”). At reference independent claims 1, 10, and 12 of Marshall, and at dependent reference claim 61, Marshall claims the formulation is both “stable” and “suitable for lyophilization”, meaning that said “stable” formulation is in a liquid state. Reference claims 93 and 94, respectively, note that the formulation is lyophilized prior to storing (e.g. in a liquid state) or is reconstituted after storing (e.g. placed back into a liquid state). Reference claims 98-100 note testing the claimed formulations over a period of time for loss of AAV infectivity, wherein the periods of time are 1 year or more, and reference claim 103 notes the formulation may be stored at -80°C, -70°C, -20°C, 4°C, 20°C, 25°C, 30°C, 35°C, or 40 °C. Marshall therefore teaches a liquid pharmaceutical formulation as outlined in instant claim 13.
Marshall teaches the composition may comprise at least 1.8E+13 GC/mL (¶[0135]; instant claim 18) and would comprise a pH between about 6.5 and 8.0, or between about 7.2 and 7.8 (¶[0114]; instant claims 14-15). Marshall teaches the rAAV may comprise and encode a transgene (¶[0202]; instant claim 25) and may comprise a capsid protein from a single AAV serotype, chimeric capsid proteins, or capsid proteins from multiple AAV serotypes, wherein the serotypes are selected from AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV-11, AAV- 12, AAV- 13, AAV- 14, AAV-15 and AAV-16, rAAV.rh8, rAAV.rhlO, rAAV.rh20, rAAV.rh39, rAAV.Rh74, rAAV.RHM4-l, AAV.hu37, rAAV.Anc80, rAAV.Anc80L65, rAAV.7m8, rAAV.PHP.B, rAAV2.5, rAAV2tYF, rAAV3B, rAAV.LK03, AAV.HSC1, AAV.HSC2, AAV.HSC3, AAV.HSC4, AAV.HSC5, AAV.HSC6, AAV.HSC7, AAV.HSC8, AAV.HSC9, AAV.HSC10 , AAV.HSC11, AAV.HSC12, AAV.HSC13, AAV.HSC14, AAV.HSC15, or AAV.HSC16 (¶[0203-0212]; instant claims 35-36). The rAAV may comprise inverted terminal repeats (ITRs), wherein the transgene encoded by the rAAV is flanked by the AAV ITRs (¶[0211][0217]; instant claim 33). Marshall teaches AAV can be used to transduce non-dividing as well as dividing cells and is ideal for gene therapy, as many AAV have long-term robust transgene expression as well as the ability to target different tissues and can be engineered to evade pre-existing immunity in the human host (¶[0003-0004][0234]; instant claims 37-38, 43). Marshall teaches the use of the rAAV comprising transgenes to treat human subjects for a variety of diseases and disorders (¶[0003][0016][0195]; instant claim 41). Marshall teaches formulation of the AAV compositions (Examples 1-7 starting at ¶[0157]; instant claim 44) and that said compositions may be stored at -80°C, -70°C, -20°C, 4°C, 20°C, 25°C, 30°C, 35°C, 37°C or 40 °C (¶[0244][00114][0100-0120]; NB: there are multiple ¶[0120] in this document; the specific paragraph references the storage temps.; instant claim 46).
For at least these reasons, Marshall teaches the limitations of instant claims 13-15, 18, 25, 33, 35-38, 41, 43-44, and 46, and anticipates the invention encompassed by said claims.
Response to Arguments
Applicant's arguments filed 12/24/2025 have been fully considered but they are not persuasive.
Applicant argues that Marshall focuses on the stability of lyophilized formulations, and does not envision stable liquid formulations. Marshall discloses at multiple instances throughout their disclosure that the formulation is a liquid formulation, or a reconstituted formulation from a lyophilized formulation (¶[0010][48.][0133] preceding and including Sect. 4.1 “Illustrative Embodiments 4.1.1. Set 1”). At reference independent claims 1, 10, and 12 of Marshall, and at dependent reference claim 61, it is not claimed that the formulation is lyophilized, but is a formulation that is both “stable” and “suitable for lyophilization”, meaning that said “stable” formulation is in a liquid state. Reference claims 93 and 94 respectively note that the formulation is lyophilized prior to storing or is reconstituted after storing. Reference claims 98-100 note testing the claimed formulations over a period of time for loss of AAV infectivity, wherein the periods of time are 1 year or more, and reference claim 103 notes the formulation may be stored at -80°C, -70°C, -20°C, 4°C, 20°C, 25°C, 30°C, 35°C, or 40 °C. Therefore, the arguments regarding Marshall focusing on only teaching lyophilized formulations, and only focusing on the stability of lyophilized formulations, is not persuasive.
For at least these reasons, the rejection is 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.
(Rejection maintained in part and extended – necessitated by amendment.) Claim 28 remains rejected under 35 U.S.C. 103 as being unpatentable over Marshall as applied to claims 13-15, 18, 25, 33, 35-38, 41, 43-44, and 46 above, and further in view of Patzke et. al. (WO2020069461A1, Pub. 04/02/2020; hereafter “Patzke”.) Note that the rejection over Fiedler is withdrawn in light of the amendments to the claims removing Fiedler as 35 USC 102 art, and the rejection is withdrawn over claims 1-2, 4, 8, and 11 in light of the cancellation of said claims.
The Prior Art
The teachings of Marshall have been set forth supra. While Marshall teaches rAAV which encode a transgene for therapeutic use, Marshall fails to explicitly teach that the transgene encodes frataxin (FXN). However, engineering a rAAV to encode FXN was taught in the art, as evidenced by Patzke.
Patzke teaches compositions and methods for enhancing the expression of frataxin (FXN) in vitro and/or in vivo, along with delivery of FXN via administration of an rAAV encoding FXN (entire document; see abstract; reference claim 1.) Patzke teaches an AAV vector genome comprising: a 5' inverted terminal repeat (ITR), an engineered promoter, a payload region and a 3' ITR; wherein the payload region encodes a frataxin (FXN) protein (reference claim 1), as well as pharmaceutical compositions which comprise this rAAV-FXN vector (reference claim 154). Patzke teaches this rAAV may be used to treat neurological or neuromuscular disorders, such as Friedreich’s Ataxia (reference claims 168-169.)
Given the teachings of Marshall, one of skill in the art would be apprised as to rAAV compositions for delivery of transgenes to a subject. Given the teachings of Patzke, one of skill in the art would be apprised as to the delivery of FXN via a rAAV vector. Therefore, arriving at the limitations of instant claim 28 would be obvious to a skilled artisan, given the combined teachings of Marshall and Patzke.
It would have been obvious to one of ordinary skill in the art to modify the methods and compositions taught by Marshall in order to deliver a specific transgene for treatment of a specific disorder, such as delivery of FXN via rAAV. One would have been motivated to do so, given the suggestion by Patzke that rAAV could be engineered to deliver and express FXN to a subject in need. There would have been a reasonable expectation of success, given the knowledge that Patzke engineered a rAAV which expressed FXN, and also given the knowledge that said rAAV could be used in subjects, such as humans, for gene therapy, as taught by Marshall and Patzke. Thus the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
(Rejection maintained in part and extended – necessitated by amendment.) Claim 34 remains rejected under 35 U.S.C. 103 as being unpatentable over Marshall as applied to claims 13-15, 18, 25, 33, 35-38, 41, 43-44, and 46 above, and further in view of Hirsch et. al. (US20140271551A1, Pub. 09/18/2014; hereafter “Hirsch”.) Note that the rejection is withdrawn over claims 1-2, 4, 8, and 11 in light of the cancellation of said claims.
The rationale behind this rejection was presented in a previous Office action and will not be repeated herein.
Response to Arguments
Applicant's arguments filed 12/24/2025 have been fully considered but they are not entirely persuasive.
As noted, the teachings of Fiedler have been withdrawn. Arguments regarding these teachings are therefore moot and will not be addressed herein.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
With respect to the teachings of Marshall, Applicant again presents the argument that Marshall focuses on lyophilized, not liquid formulations. Said argument was unpersuasive for the reasons set forth supra.
Applicant also states that Marshall provides “no disclosure regarding the stability over 12 months of liquid AAV. As set forth supra, Marshall teaches liquid and lyophilized formulations, and teaches that one would assess the stability of said formulations over time through various means, testing the formulations over days, weeks, or months, as well as testing the stability at 1, 2, and 3 years (reference claims 97-100.) Marshall also teaches that said formulation would be stored at -80°C, -70°C, -20°C, 4°C, 20°C, 25°C, 30°C, 35°C, or 40 °C (reference claim 103.) Marshall even teaches the storage may be up to 4-5 years (¶[0095-0096]), and would maintain that stability over the length of time (¶[0099]). Therefore, this argument is not persuasive.
Applicant argues that Marshall teaches away from the use of histidine and sodium chloride (NaCl). With respect to histidine, applicant points to ¶[0171](NB: this is the 3rd paragraph [0171] out of 3 noted in the specification) and notes that the histidine buffer and phosphate buffer formulations were less stable than the Tris buffer. However, it is not assessed as to what other components were in these formulations (e.g. what AAV serotype, what other stabilizers, excipients, components, etc.) and this formulation was not stored at 5 deg C for 12 months, but instead at 25 deg C (about room temperature) for 6 months after being lyophilized. Therefore, this is not a teaching away for the conditions as instantly claimed. In fact, Marshall continues to focus on histidine as the main buffer after listing other known buffers in the art (¶[0110] at Sect. 6.2.2 “Buffering Agents”).
With respect to NaCl, at ¶[0171](NB: this is the first of three ¶[0171] noted in the disclosure of Marshall), Marshall teaches that:
“Multivalent salts, which are made up of multiply charged ions having higher ionic strength (per molecule excipient added compared to mono-sodium chloride), may inhibit AAV aggregation while minimizing crystallization. As such, rAAV formulated compositions containing salts other than mono-sodium chloride that maintain the amorphous matrix of the composition are potentially useful.”
Marshall does not teach that NaCl should be avoided, but that potentially other salts may be more useful. Applicant points to the specification at ¶[0164-0166] and notes that Marshall teaches the crystalline salt (NaCl) promotes AAV genome release, but fails to note the work-around provided by Marshall in overcoming this, which is inclusion of a sugar or other component that inhibits crystallization formation reduces viral genome release upon freezing (see ¶[0164][0167-0168].) Marshall notes that the art has recognized that crystallization of NaCl during freezing and annealing can be inhibited by other excipients, and notes that the use of sucrose inhibited the crystallization of NaCl (¶[0182-0183]). Marshall notes the reason NaCl needs to be in the solution is to prevent particle aggregation, with the ionic strength of the solution needing to be 90 mM or greater for AAV8, and that the minimum ionic strength necessary is serotype-dependent (¶[0135-0136], Figs. 2-3.) Therefore, Marshall does not teach away, but teaches work-arounds for side-effects of higher NaCl in the solutions, as NaCl is required. Therefore, this line of argument is not persuasive.
Applicant argues surprising and/or unexpected results. Such surprising results are not commensurate in scope with the instant claims, as the solutions tested in Examples 1-7 had unknown AAV serotype(s)(¶[0193] denotes “Clade F capsid material” but does not specifically identify the AAV serotype, clade F can include AAV9 and hematopoietic stem cell-derived AAVs (e.g. AAVHSC1-17)) at different pHs. The Formulations 1-6 in Table 1 did not appear to comprise histidine in any form (e.g. as a buffer or additive), and instead used sodium phosphate buffer. Table 2 compared histidine to citrate buffers, and kept the pH and concentration of Poloxamer 188 and NaCl constant while varying sucrose vs. trehalose as the sugar. Formulation 9 buffer, the buffer most closely associated with that claimed in the instant claims, did not appear to have variations on the NaCl or Poloxamer 188 concentrations tested, nor variations on the concentration of the histidine buffer, and it is unclear how the pH of this buffer was “adjusted” in Example 5 at ¶[0193] (e.g. what was added to raise/lower the pH), so it is unclear that said claimed solution would exert the same stability at the same temperature for any AAV serotype. As noted supra by Marshall, each AAV has their own unique issues regarding particle stability, so proof of stability with one solution for one AAV serotype does not imply that same stability will be extended to all other AAV serotypes. Such examples provided for in the specification are not exemplary of the range of compositions claimed, and the criticality of components necessary to arrive at the surprising and/or unexpected results have not been clearly pointed out. Therefore, this line of argument is not persuasive.
Applicant argues that Patzke and Hirsch fail to cure the deficiencies of Marshall. As Marshall was not determined to be deficient, and Patzke and Hirsch clearly teach the components Marshall fails to teach, such arguments are not persuasive. No further arguments regarding Patzke or Hirsch were presented.
For at least these reasons, the rejections have been maintained, and the claims are still determined to be obvious for the reasons set forth in this and in the previous Office action.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 RACHEL B GILL whose telephone number is (571)272-3129. The examiner can normally be reached on M to F 8:00 AM to 5:00 PM Eastern.
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/RACHEL B GILL/
Primary Examiner, Art Unit 1671