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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 24th, October, 2025 has been entered.
Claim Status
Claims 1-3 and 58 are pending.
Claims 1-3 and 58 are under examination.
Withdrawn Claim Rejections - 35 USC § 112(a)
Scope of Enablement
The rejection of claims 1-3 and 58 under 35 U.S.C. 112(a) because the full scope of the claims was not enabled as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
The rejection of claim 62 under 35 U.S.C. 112(a) because the full scope of the claims was not enabled as set forth in the previous office action is withdrawn in view of the cancellation of the claim.
New 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 1-3 and 58 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 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 enabled 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 in the previous office action, 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.
Examiner’s Remark
Applicant’s amendments necessitated a new grounds of rejection under 35 U.S.C. 112a above because the claims are not enabled and therefore, arguments directed to the previous rejection under rejection under 35 U.S.C. 112a because the full scope of the claims was not enabled are moot. Nevertheless, for the sake of compact prosecution, arguments considered pertinent to the new grounds of rejection are addressed below.
Response to Arguments
Applicant’s arguments, filed 24th, October, 2025, have been fully considered but are not found persuasive.
Applicant argues “In the Office Action, the Examiner alleges that the claimed method must enable "all functional results of the claimed method" However, the amended claims do not require any functional results. Instead, amended claim 1 only requires two active steps- intravenous injection of a first rAAV comprising SEQ ID NO: 9 or 10, and intravenous injection of a second rAAV comprising SEQ ID NO: 11 or 12- and is devoid of any functional limitations. Thus, the Examiner's requirement that the claims enable "all functional results" improperly imports functional limitations into the claims and renders the Examiner's alleged prima facie finding of lack of enablement deficient. For at least this reason, the rejection should be withdrawn.” (pg. 5). Applicant argues “Proper analysis for enablement should be limited only for the two active steps of the amended claims” (pg. 5). Applicant argues “The specification further provides guidance for administering such rAAVs to other mammalian subjects, such as humans” (pg. 5).
In response, the examiner acknowledges that instant claims do not recite a functional result. Therefore, as discussed above, because no functional result is recited, instant claims encompass all possible functional results as well as no result of the claimed method. The issue at hand with respect to enablement is not whether one of ordinary skill could perform the steps of the method as claimed. The issue with respect to enablement is that the instant specification does not enable all uses ( which encompass all functional results) of the claimed method and additionally the issue with respect to enablement is the specification does not enable a use or all uses for the claimed method in the human subject as claimed. The instant specification teaches only one use of the claimed method, which is the functional result of in increased β- galactosidase enzyme activity over 40-fold compared to a mouse that has been administered PBS control. Further this use is specific to a mouse model which cannot be predictably translated to a human subject as stated above.
Applicant is directed to MPEP 2100 (a) which states that 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 2164.01(a)). In the instant case, the specification teaches one use of the claimed method in a mouse model while instant claims encompass all uses of the claimed method in a human subject. Because the specification does not evidence the one result correlates from mice to humans, and the art of record indicates that methods of administering AAVs are not predictably translated from mouse models to humans (see above), the instant specification does not enable a use or all possible uses of the claimed method in human subjects and therefore one of ordinary skill would not be able to use the claimed method in human subjects without undue experimentation.
Applicant argues “An in vitro or in vivo animal model example in the specification, in effect, constitutes a "working example" if that example "correlates" with a disclosed or claimed method invention. 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. The Examiner has provided no evidence to rebut the 'correlation' between the administration of rAAVs to the mouse model described in Examples 1-3 of the specification and administration of the recited rAAVs in human subjects. Furthermore, the instant specification discloses several well-known modalities of administering therapeutic agents to a subject. Based on the knowledge in the art and the disclosures of the instant specification, a person of ordinary skill in the art would not have been required to conduct an undue amount of experimentation to perform the two active steps if rAAV intravenous administration recited in the amended claims” (pg. 5-6).
In response, as discussed above, the issue of enablement is that the specification does not discloses an enabled use for the method in humans. Further, the instant specification has not provided a nexus to evidence that the enabled result/use of increased β- galactosidase enzyme activity over 40-fold compared to a mouse that has been administered PBS control correlates with a human subject. As discussed above, the art of record of Colella evidences 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.) and the art of Collela further evidences that methods comprising administering AAV viruses to subjects can arrive at unpredictable results because 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, in view of the specification and the art, the disclosed use of increased β- galactosidase enzyme activity over 40-fold compared to a mouse that has been administered PBS control does not appear to predictably correlate to a human subject and therefore the instant specification fails to enabled uses of the claimed method in human subjects as encompassed by instant claims.
Claim Rejections - 35 USC § 112(b)
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 2-3 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 2 recites “the isolated nucleic acid encodes a β-galactosidase protein, wherein the ~-galactosidase protein is a human GLB protein (hGLB 1 ).” However, claim 1, upon which claim 2 depends, already recites the narrower limitation that the first isolated nucleic acid comprises SEQ ID NO: 9 which encodes a specific human GLB protein (hGLB1).
Similarly, claim 3 recites “the isolated nucleic acid encodes a cathepsin protein, wherein the cathepsin protein is a human cathepsin A protein (CTSA).” However, claim 1, upon which claim 3 depends, already recites the narrower limitation that the first isolated nucleic acid comprises SEQ ID NO: 11 which encodes a specific human cathepsin A protein (CTSA).
Regarding claims 2-3, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation is considered indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). Note the explanation given by the Board of Patent Appeals and Interferences in Ex parte Wu, 10 USPQ2d 2031, 2033 (Bd. Pat. App. & Inter. 1989), as to where broad language is followed by "such as" and then narrow language. The Board stated that this can render a claim indefinite by raising a question or doubt as to whether the feature introduced by such language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Note also, for example, the decisions of Ex parte Steigewald, 131 USPQ 74 (Bd. App. 1961); Ex parte Hall, 83 USPQ 38 (Bd. App. 1948); and Ex parte Hasche, 86 USPQ 481 (Bd. App. 1949). Therefore, because claims 2 and 3 each recite a broader limitation from the claim upon which they depend, the scope of claims 2 and 3 are indefinite.
Conclusion
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.
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/BRIANA N EBBINGHAUS/Examiner, Art Unit 1632 /VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632