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 .
Claim Status
Claims 1 and 58 are pending.
Claims 1 and 58 are under examination.
Moot Claim Rejections - 35 USC § 112(a)
Enablement
The rejection of claims 2-3 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement as set forth in the previous office action is moot in view of the cancellation of these claims.
Maintained Claim Rejections - 35 USC § 112(a)
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 and 58 stand rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Wands Factors
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The Court in Wands states: “Enablement is not precluded by the necessity for some 'experimentation.'” Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single simple factual determination, but rather is a conclusion reached by weighing many factual considerations.” (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
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) (see MPEP 2100 (a)).
Breadth of the Claims
Instant claims encompass:
A method comprising simultaneously administering to a human subject, the administration comprising:
intravenously injecting the subject with a first recombinant adeno-associated virus (rAAV) comprising an AAV9 capsid protein and a first isolated nucleic acid that comprises the nucleotide sequence set forth in SEQ ID NO: 9 or 10; and
intravenously injecting the subject with a second rAAV comprising an AAV9 capsid protein and a second isolated nucleic acid that comprises the nucleotide sequence set forth in SEQ ID NO: 11 or 12.
This encompasses human subjects. Since no specific purpose, intended use, or result is recited, this encompasses all possible results of the claimed method steps including no result or use and all possible purposes or intended uses of the claimed method results.
Applicant is directed to MPEP 2164.01 which states that "[i]f a patent claims an entire class of processes, machines, manufactures, or compositions of matter, the patent’s specification must enable a person skilled in the art to make and use the entire class….The more one claims, the more one must enable." Id. In the instant case, the entire class of processes comprising these method steps is not enabled because the specification does not enable all possible results of the claimed method and more specifically the specification does not enable a use or all possible uses in human subjects as claimed. Therefore, the specification does not teach one of ordinary skill how to use the claimed method to arrive at all possible results. The instant specification enables only one result or use in mice, and does not enable results or uses in human subjects. This is discussed further below.
Direction or Guidance Presented
While the specification and working examples contemplate a method that administers to humans, the specification only provides guidance in mice (Examples 1 and 3).
While contemplating methods comprising simultaneously administering to a subject the claimed vectors, Applicant provides limited guidance on the results and uses of the claimed method steps which only apply to mouse subjects (Examples 1 and 3).
Present Working Examples
Example 1 - Administration of β-galactosidase and Cathepsin A in mice (pg. 29)
in vivo Mouse Model
Subject: C57BL/6 mice
Administration route: injection
It is noted that Example 1 discloses injection, but does not clearly state what type of injection was used.
Dose 2.25 x 1011 vg of each AAV9 vector
Mice were injected with AAV9-hGLB 1 (human β- galactosidase) or AAV9-mGLB1 (mouse human β galactosidase) under operative control of a CAG promoter (FIG. 8 and FIG. 9).
Example 2 - Co-administration of/β-galactosidase and Cathepsin A in mice (pg. 30)
in vivo Mouse Model
Subject: C57BL/6 mice
Administration route: tail vein injection
Dose 1 x 1012 vg /AAV via the tail vein in a total of 250 L
Mice were injected with recombinant AAV9 vectors encoding human GLB 1 (β-galactosidase protein) and/or either human or mouse CTSA (Cathepsin A, also referred to as PPCA) genes operably linked to a CAG promoter (FIG. 10 and FIG. 11).
Results: The co-expression of either mouse or human Cathepsin A with human β-galactosidase significantly increased liver β-galactosidase enzyme activity (FIG. 4). Expression of human β galactosidase increased serum enzyme activity (FIG. 5), and co-expression of either mouse or human Cathepsin A with human β -galactosidase increased β - galactosidase enzyme activity over 40-fold compared with PBS (control).
Example 3 - Increased expression of mature β-galactosidase expression in liver by co- administration of AAV9 vectors encoding GLB1 and Cathepsin A (pg. 30)
in vivo Mouse Model
Subject: C57BL/6 mice
Administration route: injection
It is noted that Example 3 discloses injection, but does not clearly state what type of injection was used.
Total and mature hGLB 1 was measured from liver of C57BL/6 mice injected with: (1)PBS, (2)mouse PPCA, (3)human PPCA, (4)human GLB 1, (5)human GLB 1+mouse PPCA, or (6) human GLB 1 + human PPCA.
Results: The presence of precursor (86 kilodalton (kDa)) and mature (66 kDa) GLB1 protein was analyzed by western blot with an antibody against human GLB1. The mature protein to precursor protein ratio increased dramatically in animals co-administered human GLB1 and PPCA (either mouse or human sequences) (FIGs7A and 7B).
Figure 7B is copied below:
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State of the Art and Unpredictability of the Art
The methods of practicing the claimed invention are not well established. As stated above, the instant specification only teaches mouse subjects and does not teach results other than “the method results in increased β- galactosidase enzyme activity over 40-fold compared with PBS control in mice”(see pg. 30 and Figure 6) which is specific to the mouse subject. The specification does not provide a nexus to indicate that the result achieved would translate to the claimed human subject.
Subject Types
Regarding the cell type, Applicant’s claims encompass human subject types. Applicant is directed to the art of Colella et al. (Mol Ther Methods Clin Dev. 2017 Dec; henceforth “Colella”). Colella teaches that the transduction ability of AAV vectors from results in mice and other small-animal models may not always be extrapolated to large-animal models and humans (pg. 94 col. 1 2nd para).
Since extrapolation of AAV vectors from mice to large animal models and humans is not predictable, Applicant is not enabled for all possible results of the claimed recited method steps in human subject types.
Results of the claimed method
Instant claims do not recite or require a functional result and do not recite or require a purpose or intended use. As stated above, Applicant has only disclosed one result of the method in mice specifically, which is the result that administration of the first rAAV and the second rAAV increases β - β- galactosidase enzyme activity over 40-fold compared with PBS control (see Examples 3-4 and Figure 6)
Further, regarding functional results, it is well known in the art the methods comprising administering AAV viruses to subjects can arrive at unpredictable results. Applicant is directed to the art record of Colella et al. (Mol Ther Methods Clin Dev. 2017 Dec; henceforth “Colella”). Colella evidences results of AAV administration are unpredictable. Specifically, Colella evidences high-doses of AAV can result in a detrimental effect of the ongoing immune response against the AAV-transduced cells on transgene expression, a significant loss in transduced cells, and loss of transgene expression concomitant to increase in liver enzymes (pg. 91).
Therefore, because the results and effects of the claimed method go beyond the disclosed functional result (which is specific to mouse subjects), and the state of the art evidences these results are not predictable, Applicant is not enabled for all possible results of the claimed method.
Unpredictability of the Art and Quantity of Experimentation
As the state of the art demonstrates, the obstacles that hinder the use of the claimed method embodiments and results thereof are not easy tasks to be done or solely routine experimentation to enable particular embodiments of the claimed method. The type of experimentation would require new methodologies. This level of experimentation goes beyond what would be routine optimization know at the time of filing. As such, the amount of experimentation would be undue.
The physiological art is recognized as unpredictable (MPEP 2164.03). As set forth in In re Fisher, 166 USPQ 18 (CCPA 1970), compliance with 35 USC 112(a) requires: “That scope of claims must bear a reasonable correlation to scope of enablement provided by specification to persons of ordinary skill in the art; in cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws; in cases involving unpredictable factors, such as most chemical reactions and physiological activity, scope of enablement varies inversely with degree of unpredictability of factors involved.” Moreover, the courts have also stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in the patent application (27 USPQ2d 1662 Ex parte Maize!.). In view of the foregoing, due to the lack of sufficient guidance provided by the specification regarding the issues set forth above, the state of the relevant art, and the breadth of the claims, it would have required undue experimentation for one skilled in the art to practice the method of the instant broadly claimed invention.
Enablement - Conclusion
In conclusion, the breadth of the claims lacks enablement because the specification provides limited working examples in an in vivo mouse model, with limited results and uses of the methods that are specific to the mouse model while instant claims encompass humans. The state of the art indicates that findings in mice cannot be predictably translated to humans and the instant specification has failed to provide evidence to the contrary. The art at the time of effective filing fail to provide specific guidance that supplement to shortcomings of the specification and further teaches that the breadth of claims cannot be predictably performed. Further, a great deal of new methodology would need to be developed to enable the results and uses of the claims and this level of experimentation is undue.
Accordingly, the claims are not enabled.
Examiner’s Remark
The Examiner notes that, as set forth previously, the specification is enabling for the alternative embodiment in mouse subjects of:
A method comprising simultaneously administering to a mouse subject:
a first recombinant adeno-associated virus (rAAV) comprising an AAV9 capsid protein and a first isolated nucleic acid that comprises the nucleotide sequence set forth in SEQ ID NO: 9 or 10; and
a second rAAV comprising an AAV9 capsid protein and a second isolated nucleic acid that comprises the nucleotide sequence set forth in SEQ ID NO: 11 or 12,
wherein the administration comprises intravenous injection,
wherein the method results in increased β- galactosidase enzyme activity over 40-fold compared to a mouse that has been administered PBS control.
Response to Arguments
Applicant’s arguments, filed 17th, July, 2026, have been fully considered but are not found persuasive.
Applicant argues the rejection rests on an unreasonable construction of claim 1 (pg. 3-4). Specifically, Applicant argues that “The Examiner has not identified any claim
language that imports a functional result requirement, nor justified under MPEP § 2111 why
construing the claims to encompass "all possible results" is a reasonable interpretation rather than
the broadest possible one” (pg. 3).
Applicant further specifically argues “The enablement inquiry is accordingly properly directed to whether a person of ordinary skill in the art could perform these two recited steps without undue experimentation, not to whether the specification enables every hypothetical downstream outcome” (pg. 4).
In response, as set forth previously and above, the rejection of record cites MPEP 2164.01 which states that "[i]f a patent claims an entire class of processes, machines, manufactures, or compositions of matter, the patent’s specification must enable a person skilled in the art to make and use the entire class….The more one claims, the more one must enable." Id. In the instant case, Applicant’s claim encompasses an entire class of processes which is the entire class of processes with the claimed method steps of administering the claimed components and also includes the results and uses of that entire class of processes. The examiner’s construction of the broadest reasonable interpretation of the claim is consistent with the guidance of MPEP 2164.01 concerning enablement for the reasons set forth above.
Furthermore, while a functional requirement is not explicitly stated in the claim, each claim must have an enabled use. Applicant is directed to MPEP 2164 which states that the purpose of the requirement that the specification describe the invention in such terms that one skilled in the art can make and use the claimed invention is to ensure that the invention is communicated to the interested public in a meaningful way. The information contained in the disclosure of an application must be sufficient to inform those skilled in the relevant art how to both make and use the claimed invention (MPEP 2164). As set forth above, the instant claims do not recite an enabled use for the claimed method steps and the instant specification fails to enable a use for the method steps. The issue at hand is not whether there is a specific functional requirement recited or required to be imported, but rather whether there is an enabled use for the claim. As set forth in the grounds of rejection above, the present claims as written read on any result or use since no result or use is recited in the claims.
Further in response, MPEP 2164 sets forth the enablement requirement and states that the purpose of the requirement is that the specification describes the invention in such terms that one skilled in the art can make and use the claimed invention. In the instant case, the issue with respect to enablement is whether the specification describes the invention in such terms that one skilled in the art can make and use the claimed invention. For the reasons set forth above, the specification does not enable a use or result of the claimed method, and therefore, one skilled in the art would not be able to make and use the claimed invention. While the specification contemplates methods of treating lysosomal storage diseases in human subjects (pg. 2-3, 13, 21, 26), the specification does not enable these contemplated uses because the specification fails to provide a nexus between the mouse model data and a use in a human subject for the reasons set forth above. Furthermore, no other uses are contemplated for the claimed method.
Applicant argues “The Specification, Together with Knowledge in the Art, Enables the Claimed Steps Without Undue Experimentation” (pg. 4-5).
Applicant specifically argues “the specification provides actual working examples (Examples 1-3). MPEP § 2164.02 further provides that an in vivo animal model example "constitutes a 'working example' if that example 'correlates' with a disclosed or claimed method invention," and that such correlation "should be accepted ... unless the examiner has evidence that the model does not correlate" (pg. 4).
Applicant further argues “Mendell et al., N. Engl. J. Med. 377:1713 (2017), reports IV infusion of an AAV9-packaged transgene to fifteen human patients, using the same capsid serotype and route of administration claimed here. Nathwani et al., N. Engl. J. Med. 365:2357 (2011), demonstrates that a single peripheral-vein AAV infusion produced sustained therapeutic transgene expression in human patients via liver-directed gene transfer. Even to the extent the Examiner's enablement inquiry extends to whether the claimed method produces a result in humans, Mendell reports that clinical results reflected the direction of the preclinical mouse model, and Nathwani confirms that liver-directed AAV gene transfer produced sustained therapeutic transgene expression in humans” (pg. 5).
Applicant further argues “The Examiner's reliance on Colella is misplaced. Colella' s observation that liver transduction results in mice "may not always" be extrapolated to humans is a qualified generality supported only by data on a different serotype (AA V2 tyrosine mutants) in a different species (dogs). Colella itself acknowledges that "studies in small- and large-animal models and in humans have demonstrated that it is possible to target hepatocytes with adequate efficiency using intravenously administered AAV vectors" (p. 89, citing Nathwani). Similarly, the immune responses and liver enzyme elevations the Examiner cites from Colella are drawn from the same Nathwani study, which Colella characterizes as "an important stepping-stone" showing "that it is possible to monitor liver enzymes to design prompt interventions" (p. 92). Colella does not constitute evidence that the mouse model used in the specification does not correlate with the claimed method of intravenous rAAV administration in human subjects.” (pg. 5).
In response, concerning animal models, MPEP § 2164.02, cited by Applicant, also states that if the art is such that a particular model is recognized as correlating to a specific condition, then it should be accepted as correlating unless the examiner has evidence that the model does not correlate. Even with such evidence, the examiner must weigh the evidence for and against correlation and decide whether one skilled in the art would accept the model as reasonably correlating to the condition. In re Brana, 51 F.3d 1560, 1566, 34 USPQ2d 1436, 1441 (Fed. Cir. 1995) (reversing a USPTO decision based on finding that in vitro data did not support in vivo applications). The Examiner acknowledges that a rigorous or an invariable exact correlation is not required, as stated in Cross v. Iizuka, 753 F.2d 1040, 1050, 224 USPQ 739, 747 (Fed. Cir. 1985) (see MPEP § 2164.02 (II)).
In the instant case, the Examiner has weighed the evidence for and against correlation and decide whether one skilled in the art would accept the model as reasonably correlating to the condition and has decided that one of ordinary skill would not accept the model as reasonably correlating to the condition because the state of the art indicates that gene therapy is unpredictable in humans as compared to mouse models for the reasons set forth above. The specific cited arts of Mendell, Nathwani, and Colella are further discussed below.
Furthermore, Applicant’s specification does not enable a result in humans and only discloses a mouse model. As discussed below, and as set forth above, the mouse model disclosed by Applicant does not enable a use in humans because the state of the art is that the results of gene therapy do not predictably translate from mouse to humans. As discussed above, the mouse model had the result of increased β- galactosidase enzyme activity over 40-fold compared to a mouse that has been administered PBS control as a gene therapy. Applicant’s specification sets forth that the disease of GM-1 gangliosidosis shows a deficiency in β-galactosidase (pg. 1). As set forth above, Applicant’s specification contemplates uses for treatment of lysosomal storage diseases including GM-1 gangliosidosis (pg. 2-3, 13, 21, 26). However, Applicant fails to provide a nexus between the result obtained in a mouse model and any enabled use of a method of treating symptoms of a disease in humans. Furthermore, the mouse model disclosed by Applicant is a wild-type mouse and not a disease model. Applicant has not provided a nexus that would indicate that the results of the specification in a wild-type mouse would represent the results of the method in a human with a specific disease. Correlation between mouse models and human subjects is discussed further below.
In response, concerning the Mendell and Nathwani references, it is first noted that the cited references of Mendell and Nathwani made of record and are cited in the IDS filed on 17th, July, 2026. As set forth above, the examiner must weigh the evidence for and against correlation and decide whether one skilled in the art would accept the model as reasonably correlating to the condition. In re Brana, 51 F.3d 1560, 1566, 34 USPQ2d 1436, 1441 (Fed. Cir. 1995) (see MPEP § 2164.02).
In response, whether the state of the art, in conjunction with the specification, enables claims is determined on a case by case basis. In the instant case, the state of the art recognizes that gene therapy is unpredictable among species and between species. This is evidenced by the Colella reference as discussed above. In order to complete the art of record and rebut Applicant’s arguments, Applicant is additionally directed to the post-filing art of Xu (Acta Biochim Pol. 2026 Mar 26:73:15939. eCollection 2026.) which evidences that despite extensive preclinical validation, AAV programs often encounter translational gaps when advancing from rodents to non-human primates (NHPs) and ultimately to humans (abstract). Xu evidences species barriers manifest at multiple levels: capsid binding to glycans or protein receptors, intracellular processing and innate sensing, vector dissemination across tissue barriers, and adaptive immune responses that differ in magnitude and specificity (pg. 2 col. 1 2nd para.). Xu evidences such effects are not isolated phenomena but recur across tissues and vector classes (pg. 2 col. 1 2nd para.). Xu evidences a prominent example is the strain-dependent enhancement of central nervous system transduction by AAV-PhP.B, which depends on LY6A expression in select C57BL/6J mouse strains and fails in other strains and in NHPs (pg. 2 col. 1 2nd para. citing references from 2016, 2018 and 2019). Therefore, Xu evidences that the state of the art post-filing is that gene therapy is unpredictable when translating from mouse to humans and even for the same vector in different strains of the same mouse species. Because the state of the art is that these gene therapy methods are unpredictable post-filing, they cannot have been enabled or predictable as of the effective filing date of the claimed invention.
Therefore, further in response, the cited the method of Mendell which includes the step of administering an AAV8 vector by intravenous injection and results in expression of an SMN transgene (abstract) and the cited method of Nathwani which includes the step of administering an AAV8 vector by intravenous injection and results in expression of a factor IX transgene (abstract) can’t enable any and all results of the claimed structurally and functionally distinct method while the state of the art evidences that AAV gene therapy methods do not predictably result in the desired expression or result.
In response, concerning the Colella reference, the reference of Colella is cited to evidence the state of the art that gene therapy is unpredictable. While Applicant cites that Colella states that studies in small- and large-animal models and in humans have demonstrated that it is possible to target hepatocytes with adequate efficiency using intravenously administered AAV vectors" (p. 89, citing Nathwani) and “Colella characterizes as "an important stepping-stone" showing "that it is
possible to monitor liver enzymes to design prompt interventions" (p. 92) (citation of Colella by Applicant on pg. 5 of the remarks), this does not enable instant claims. The commentary that it is possible to target hepatocytes an it is possible to design prompt interventions is insufficient to enable the instant claimed method which encompasses any and all results. Furthermore, Colella is one reference that evidences the state of the art that gene therapy is unpredictable and is also unpredictable from species to species. As set forth above, this can be additionally evidenced by other references such as the reference of Xu which is made of record and discussed above.
Importantly, concerning Mendell, Nathwani, and Colella, when these references, considered with the specification and the state of the art, as whole fail to enable the instant claimed method which encompasses any and all results. As set forth above, it is maintained that the state of the art evidences gene therapy methods are unpredictable among species and between species (see Colella as well as Xu).
Therefore, the Examiner has considered the specification as well as the knowledge in the art, has weighed the evidence for and against correlation, and has decided that for the method steps of instant claims, one skilled in the art would not accept the mouse model as reasonably correlating to the method in human subjects (see In re Brana, 51 F.3d 1560, 1566, 34 USPQ2d 1436, 1441 (Fed. Cir. 1995) (see MPEP § 2164.02).
Moot Claim Rejections - 35 USC § 112(b)
The rejection of claims 2-3 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite as set forth in the previous office action is moot in view of the cancellation of these claims.
Conclusion
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.
No claim is allowable.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIANA N EBBINGHAUS whose telephone number is (703)756-4548. The examiner can normally be reached M-F 9:30 AM to 5:30 PM ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at (571) 272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BRIANA N EBBINGHAUS/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
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