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 1-14, 16-20, 32, and 36 are pending. Claims 14 and 36 are withdrawn. Claims 1-13, 16-20, and 32 are presently considered.
Power of Attorney Not of Record
A POA has not been filed in the instant case (see Filing receipt mailed June 2, 2026). Applicant is advised that in the absence of a POA, Examiner will be unable to conduct interviews or contact the Applicant if allowable subject matter is identified during prosecution.
Election/Restrictions
Applicant's election with traverse of Group I1 (original claims 1-14, 16-20, and 32) and the species of AAV2-NS vector (AAV2-CAG2-eGFP-T2A-hNS-WPRE), encoding mutant human neuroserpin M363R (SEQ ID NO: 2), in the reply filed on 8/18/2026 is acknowledged. The traversal is on the ground(s) that “the search and examination burden on the Examine is not undue”. This is not found persuasive because it is undisputed that the pending inventions and species lack inventive step in view of the prior art (see Requirement mailed 6/22/2026 at 7-9), Group I encompasses trillions of species2, and Applicant has not identified that such species are obvious variants of one another.
The requirement is still deemed proper and is therefore made FINAL.
The originally elected species is understood to be AAV2-NS vector (AAV2-CAG2-eGFP-T2A-hNS-WPRE), but the complete sequence for the vector was not provided or identified; no catalog number, etc. was provided. The vector is understood to encode mutant human neuroserpin M363R (SEQ ID NO: 2), wherein SEQ ID NO: 2 is
MAFLGLFSLLVLQSMATGATFPEEAIA DLSVNMYNRLRATGEDENILFSPLSIALAMGMMELGAQGSTQKEIRHSMGYDSLKNGEEFSFLKEFSNMVTAKESQYVMKIANSLFVQNGFHVNEEFLQMMKKYFNAAVNHVDFSQNVAVANYINKWVENNTNNLVKDLVSPRDFDAATYLALINAVYFKGNWKSQFRPENTRTFSFTKDDESEVQIPMMYQQGEFYYGEFSDGSNEAGGIYQVLEIPYEGDEISMMLVLSRQEVPLATLEPLVKAQLVEEWANSVKKQKVEVYLPRFTVEQEIDLKDVLKALGITEIFIKDANLTGLSDNKEIFLSKAIHKSFLEVNEEGSEAAAVSGMIAISRRAVLYPQVIVDHPFFFLIRNRRTGTILFMGRVMHPETMNTSGHDFEEL
The species is understood to correspond to the Example at pages 36-38 of the specification, and Figures 21-22, wherein AAV2 is Adeno-associated virus backbone serotype 2, NS is human neuroserpin cDNA (BC018043, SEQ ID NO: 33, Figure 23-24), CAG2 is chicken β-actin rabbit beta-globin (CBA) hybrid promoter, eGFP is green fluorescent protein, WPRE is Woodchuck Hepatitis Virus Postranscriptional Regulatory Element; and a 2A peptide called T2A (Thoseaasigna virus 2A) was present, which facilitates stoichiometric production of discrete protein products within a single vector through a novel “cleavage” event within the 2A peptide sequence. SEQ ID NO: 2 is understood to comprise SEQ ID NO: 34 (“MIAX3SRX1X2VL”), wherein X3 is I, X1 is R, and X2 is A. The specific sequence of the vector, or information where it may be uniquely identified or obtained, was not provided.
Although Applicant alleges that the CAG2 promoter is an “RGC specific promoter” and reads upon claim 14 (see, e.g., Reply filed 8/18/2026 at 3), this is factually incorrect, because CAG is a ubiquitous promoter (see LeBec et al3. at 806 at col I at 1st full ¶), and is not specific to retinal ganglion cells; therefore the originally elected species does not read upon original claim 14. Accordingly, the originally elected species is understood to read upon claim 1-13, 16-20, and 32.
Following extensive search and examination, the originally elected species has been deemed anticipated and/or obvious in view of the prior art as applied below. Per MPEP § 803.02(III)(A),
Following election, the Markush claim will be examined fully with respect to the elected species and further to the extent necessary to determine patentability. Note that where a claim reads on multiple species, only one species needs to be taught or suggested by the prior art in order for the claim to be anticipated or rendered obvious...
If the Markush claim is not allowable, the provisional election will be given effect and examination will be limited to the Markush claim and claims to the elected species, with claims drawn to species patentably distinct from the elected species held withdrawn from further consideration.
Accordingly, claims 1-13, 16-20, and 32 are rejected in view of the originally elected species and claims that do not read upon the originally elected species are withdrawn.
Claim 36 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 8/18/2026.
Claim 14 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (species) requirement in the reply filed on 8/18/2026.
Claims 1-13, 16-20, and 32 are presently considered.
Denial of Priority
The priority claim to AU2021902179 (filed 7/15/2021) is acknowledged; but priority to AU2020904767 (filed 12/21/2020) is denied as explained below.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, AU2020904767 (filed 12/21/2020) fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
The MPEP states that "[w]hile there is no in haec verba requirment, . . . . claim limitations must be supported in the specification through express, implicit, or inherent disclosure." See MPEP § 2163.
Lack of Express Support
Claim 1 is representative of the pending claim scope, but instant claim 1 as filed 5/18/2026 does not literally appears in AU’767, and therefore the claims lack literal support in AU’767.
As a specific example, instant claim 1 recites SEQ ID NO: 34 (“MIAX3SRX1X2VL”), which is utilized to define the claim scope, wherein X1 is not M, X2 is M or A, and X3 is I, V, or N (see instant claim 1). However, SEQ ID NO: 34 (“MIAX3SRX1X2VL”) does not literally appear in the AU’767 disclosure, and therefore AU’767 does not literally define an invention synonymous or equivalent to the invention recited at instant claim 1.
Accordingly, AU’767 fails to provide literal support for the pending claim scope that is synonymous or equivalent in scope.
Lack of Implicit or Inherent Support
The MPEP states that "[w]hile there is no in haec verba requirment, . . . . claim limitations must be supported in the specification through express, implicit, or inherent disclosure." See MPEP § 2163. In the absence of express support, the relevant issue is whether or not the claimed invention is supported by AU’767 through implicit or inherent disclosures.
Upon review, zero inherent or implicit support commensurate in scope with the metes and bounds of instant claim 1 is found in AU’767, at least because AU’767 fails to teach or disclose SEQ ID NO: 34 (“MIAX3SRX1X2VL”). Furthermore, the closest support appears to be a single example comprising a pSF-CAG-GFP plasmid comprising a mutated wild-type neuroserpin, wherein the sole mutation consisted of a M363R mutation (see, e.g., AU’767 at Examples on 23). Accordingly, AU’767 fails to provide literal, implicit, or inherent support for a genus that is equivalent or synonymous in scope with instant claim 1.
Accordingly, AU’767 fails to provide implicit or inherent support for the pending claim scope that synonymous or equivalent in scope, or otherwise commensurate in scope with the pending claims.
Conclusion
Accordingly, priority to AU2020904767 (filed 12/21/2020) is denied for claim 1 and all of the dependents of those claims; these claims have been accorded a priority date of July 15, 2021, which corresponds to the filing date of AU2021902179 (filed 7/15/2021).
Information Disclosure Statement
The IDS filed 6/16/2023 is acknowledged and presently considered.
It is noted that the duty of disclosure, candor, and good faith is applicable to named inventors, each attorney or agent that prepares or prosecutes, and all persons substantively involved in the preparation or prosecution of the application, and who are associated with the inventor, the applicant, an assignee, or anyone to whom there is an obligation to assign the application (see, e.g., 37 C.F.R. 1.63(c) and 37 C.F.R. 1.56). Here, it is noted that any news report, poster session, publication, dissertations, thesis, catalog numbers for vectors, etc. relevant to neuroserpin and mutants thereof, or to the specific vector(s) utilized in the instant disclosure, is relevant to the patentability of the instant invention.
It is noted that the Specification recites numerous references that have not been placed in an IDS, but are presumed to be germane to patentability by virtue of being cited in the Application. However, the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Interpretation
For purposes of examination, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
Claim 1 is representative of the pending claim scope and presently recites:
1. A vector comprising a nucleic acid comprising a nucleotide sequence encoding a mutant neuroserpin protein or a portion thereof, the mutant neuroserpin or portion thereof comprising an amino acid sequence that is at least 60% identical to the amino acid sequence of SEQ ID NO : 2, and which comprises a reactive centre loop comprising the amino acid sequence MIAX3SRX1X2VL (SEQ ID NO: 34), wherein:
X1 is an amino acid other than M;
X₂ is M or A; and
X₃ is I, V or N,
and wherein the mutant neuroserpin protein or portion thereof has serine protease inhibition activity and is at least partially resistant to oxidative inactivation.
Accordingly, claim 1 is directed to a product, namely a vector. Applicable claim interpretations are discussed below.
“Comprising” is an open-ended transitional term (see, e.g., MPEP § 2111.03(I)), wherein additional steps or components are not excluded. However, “‘[c]omprising’ is a term of art used in claim language which means that the named elements are essential” (see, e.g., id.; see also Genentech, Inc. v. Chiron Corp., 112 F.3d 495, 501, 42 USPQ2d 1608, 1613 (Fed. Cir. 1997)).
“Consisting of” excludes any elements, step, or ingredient not specified (see, e.g., MPEP § 2111.03(II)). When the phrase "consists of" appears in a clause of the body of a claim, rather than immediately following the preamble, the "consisting of" phrase limits only the element set forth in that clause; other elements are not excluded from the claim as a whole (see, e.g., MPEP § 2111.03(II)).
“Consisting essentially of” limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention (see, e.g., MPEP § 2111.03(III)). However, the instant disclosure does not explicitly define the metes and bounds of what parameters do or do not “materially affect the basic and novel characteristic(s)” of the claimed invention. Therefore, as noted at MPEP § 2111.03(III), for purposes of examination and applying prior art, absent a clear indication in the specification or claims of what the basic and novel characteristics actually are, "consisting essentially of" has been construed as equivalent to "comprising" (see, e.g., MPEP § 2111.03(III)).
Regarding the recitation at claim 1 of “has serine protease inhibition activity and is at least partially resistant to oxidative inactivation”: Claim 1 ostensibly encompasses trillions of species4, but claim 1 recites that the encoded mutant neuroserpin that “has serine protease inhibition activity and is at least partially resistant to oxidative inactivation”. It is unclear if this is a functional limitation or simply a recitation of an intended and expected result. If the phrase is a functional limitation that further limits the scope of the claims from >>trillions of species down to a smaller number, then the limitation raises issues under 35 USC 112(a) and 35 USC 112(b), because the phrase fails to correspond to a structure/function relationship on record that reasonably permits artisans to identify the metes and bounds of the claim scope. Alternatively, if the phase is a recitation of an intended and expected result, fully satisfied by any and all mutant neuroserpin “protein or a portion thereof” that satisfy the positively-recited structural limitations set forth in the body of claim 1 (i.e., any “amino acid sequence that is at least 60% identical to . . . SEQ ID NO: 2” that also comprises MIAX3SRX1X2VL as defined by claim 1), then such language would be non-limiting and properly objected as superfluous, non-limiting, and confusing. For purposes of examination, Applicant has interpreted the phrase as a functional limitation for purposes of 35 USC 112(a) and 35 USC 112(b), but as a non-limiting recitation of intended and expected results for purposes of 35 USC 103.
Regarding the recitation at claim 6 of “the serine protease inhibition activity comprises inhibition of plasmin, tissue plasminogen activator and/or urokinase plasminogen activator”: Claim 1 ostensibly encompasses trillions of species5, but claim 1 recites that the encoded mutant neuroserpin that “has serine protease inhibition activity and is at least partially resistant to oxidative inactivation”, wherein claim 6 further specifies that “the serine protease inhibition activity comprises inhibition of plasmin, tissue plasminogen activator and/or urokinase plasminogen activator”. As explained above, It is unclear if this is a functional limitation that actively limits the scope of the claims or if the phrase is simply a recitation of an intended and expected result. If the phrase is a functional limitation that further limits the scope of the claims from >>trillions of species down to a smaller number, then the limitation raises issues under 35 USC 112(a) and 35 USC 112(b), because the phrase fails to correspond to a structure/function relationship on record that reasonably permits artisans to identify the metes and bounds of the claim scope. Alternatively, if the phase is a recitation of an intended and expected result, fully satisfied by any and all mutant neuroserpin “protein or a portion thereof” that satisfy the positively-recited structural limitations set forth in the body of claim 1 (i.e., any “amino acid sequence that is at least 60% identical to . . . SEQ ID NO: 2” that also comprises MIAX3SRX1X2VL as defined by claim 1), then such language would be non-limiting, raise issues under 35 USC 112(d), and properly objected as superfluous, non-limiting, and confusing. For purposes of examination, Applicant has interpreted the phrase as a functional limitation for purposes of 35 USC §§ 112(a), 112(b), and 112(d), but as a non-limiting recitation of intended and expected results for purposes of 35 USC 103.
Additional claim interpretations are set forth below.
Claim Objections
Claim 12 is objected to because of the following informalities:
The acronym “RCG” should be spelled out at least once in the claim set.
Appropriate correction is required.
Applicant is advised that should claim 9 be found allowable, claim 10 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). Here, “consisting essentially of” is not specifically defined, and as noted at MPEP § 2111.03(III), for purposes of examination and applying prior art, absent a clear indication in the specification or claims of what the basic and novel characteristics actually are, "consisting essentially of" has been construed as equivalent to "comprising" (see, e.g., MPEP § 2111.03(III)), and therefore claims 9 and 10 appear to be substantial duplicates in scope.
Claim Rejections
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 1-13, 16-20, and 32 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 1 ostensibly claims >>trillions of species of vectors that are further limited to a narrower, genus of unknown size or metes and bounds, by the recitation of the functional limitation requiring that the species “ha[ve] serine protease inhibition activity and [are] at least partially resistant to oxidative inactivation” (see, e.g., instant claim 1). However, this functional limitation fails to correspond to a structure/function relationship of record commensurate in scope with the instant claim scope. Per MPEP § 2173.05(g),
[T]he use of functional language in a claim may fail "to provide a clear-cut indication of the scope of the subject matter embraced by the claim" and thus be indefinite. In re Swinehart, 439 F.2d 210, 213 (CCPA 1971). For example, when claims merely recite a description of a problem to be solved or a function or result achieved by the invention, the boundaries of the claim scope may be unclear. . .
Here, the claims merely recite a description of functions or results the inventor hopes and desires that the invention achieves, rather than a description of the actual structures capable of achieving the desired function; therefore the claims are indefinite per MPEP § 2173.05(g) because MPEP § 2173 identifies that the primary purpose of the requirement is to inform the public of the boundaries of what constitutes infringement of the patent, but here it is unclear what compounds do or do not infringe upon the scope of claim 1. Accordingly, although it is reasonably assumed that the limitations of claim 1 may be fully satisfied by human neuroserpin comprising a single mutation at position 363 (e.g., corresponding to position X1), zero additional guidance or structure/function teachings are presented identifying any functional sequences sharing less than 100% identity with instant SEQ ID NO: 2 that satisfies all structural and functional limitations of claim 1. This is pertinent because the metes and bounds of the claim scope may vary from >>trillions of species or may include less than ten (or even just one) species. Notably, the courts have stated that
Regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.” University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1984 (CAFC 2004) (emphasis added).
Accordingly, because it is unclear what compounds do or do not satisfy the functional limitations of claim 1, and an artisan would be unable to identify infringing from non-infringing compounds, claim 1 is rejected as indefinite.
Claim 1 recites “wherein the mutant neuroserpin protein or portion thereof . . . is at least partially resistant to oxidative inactivation”, which renders the claim scope indefinite because it raises the unanswered question, “‘at least partially resistant’ relative to what?”. Here, the phrase is a relative comparison, but fails to identify a comparator, which renders the claim indefinite. The phrase 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. Per MPEP § 2173.05(b)(II), references to an object that is variable may render a claim indefinite, and here the comparator implicitly present to determine “at least partially resistant” is left unidentified. Therefore, if the comparator is already resistant to oxidative inactivation, or if the comparator is not at all resistant to oxidative inactivation, the scope of the claim changes. Therefore, claim 1 is rejected as indefinite.
Regarding instant claim 6: Claim 1 ostensibly claims >>trillions of species of vectors that are further limited to a narrower, genus of unknown size or metes and bounds, by the recitation of the functional limitation requiring that the species “ha[ve] serine protease inhibition activity and [are] at least partially resistant to oxidative inactivation” (see, e.g., instant claim 1), wherein instant claim 6 further limits the functional limitation of claim 1 (claim 6 recites “the serine protease inhibition activity comprises inhibition of plasmin, tissue plasminogen activator and/or urokinase plasminogen activator”), but this functional limitation fails to correspond to a structure/function relationship of record commensurate in scope with the instant claim scope. Per MPEP § 2173.05(g),
[T]he use of functional language in a claim may fail "to provide a clear-cut indication of the scope of the subject matter embraced by the claim" and thus be indefinite. In re Swinehart, 439 F.2d 210, 213 (CCPA 1971). For example, when claims merely recite a description of a problem to be solved or a function or result achieved by the invention, the boundaries of the claim scope may be unclear. . .
Here, the claims merely recite a description of functions or results the inventor hopes and desires that the invention achieves, rather than a description of the actual structures capable of achieving the desired function; therefore the claims are indefinite per MPEP § 2173.05(g) because MPEP § 2173 identifies that the primary purpose of the requirement is to inform the public of the boundaries of what constitutes infringement of the patent, but here it is unclear what compounds do or do not infringe upon the scope of claim 6. Accordingly, although it is reasonably assumed that the limitations of claims 1 and 6 may be fully satisfied by human neuroserpin comprising a single mutation at position 363 (e.g., corresponding to position X1), zero additional guidance or structure/function teachings are presented identifying any functional sequences sharing less than 100% identity with instant SEQ ID NO: 2 that satisfies all structural and functional limitations of claims 1 and 6. This is pertinent because the metes and bounds of the claim scope may vary from >>trillions of species or may include less than ten (or even just one) species. Notably, the courts have stated that
Regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.” University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1984 (CAFC 2004) (emphasis added).
Accordingly, because it is unclear what compounds do or do not satisfy the functional limitations of claims 1 and 6, and an artisan would be unable to identify infringing from non-infringing compounds, claims 1 and 6 are rejected as indefinite.
Claim 8 refers to “the amino acid substitution is M363R”, which renders the claim scope indefinite because “M363R” lacks antecedent basis. There is insufficient antecedent basis for this limitation in the claim. For purposes of applying prior art, it is presumed that “M363” in “M363R” refers to numbering corresponding to wildtype human neuroserpin, and satisfied by instant SEQ ID NO: 2.
Claims 8-9 and 11refer to “the mutant neuroserpin”. There is insufficient antecedent basis for this limitation in the claim. For purposes of applying prior art, it is presumed that “mutant neuroserpin” refers to “a mutant neuroserpin protein or a portion thereof”.
Claim 11 recites the phrase “a regulatory sequence operatively linked to the nucleotide sequence encoding mutant neuroserpin for permitting expression of the mutant neuroserpin in a host cell”, wherein claim 11 recites a functional limitation attempting to define desired structures by reciting the function the structures are intended to achieve. No structure/function relationship is provided on record for this functional limitation, and the structures would necessarily vary depending on the “host cell” at issue (i.e., a stem cell, retinal cell, bacterial cell, plant cell, etc., etc. all require different “regulatory sequence” elements to achieve expression). Per MPEP § 2173.05(b)(II), references to an object that is variable may render a claim indefinite, and here the “host cell” is variable and directly impacts the claim scope. Per MPEP § 2173.05(g),
[T]he use of functional language in a claim may fail "to provide a clear-cut indication of the scope of the subject matter embraced by the claim" and thus be indefinite. In re Swinehart, 439 F.2d 210, 213 (CCPA 1971). For example, when claims merely recite a description of a problem to be solved or a function or result achieved by the invention, the boundaries of the claim scope may be unclear. . .
Here, the claims merely recite a description of functions or results the inventor hopes and desires that the invention achieves, rather than a description of the actual structures capable of achieving the desired function; therefore the claims are indefinite per MPEP § 2173.05(g) because MPEP § 2173 identifies that the primary purpose of the requirement is to inform the public of the boundaries of what constitutes infringement of the patent, but here it is unclear what compounds do or do not infringe upon the scope of claim 11, because 11 amounts to a vast and highly varied functional limitation equivalent to reciting “whatever elements are needed” without identifying what elements are actually required and present for particular host cells. Accordingly, although it is reasonably assumed that the limitations of claims 1 and 11 may be fully satisfied by AAV2 and retinal ganglion cells, zero guidance or structure/function teachings are presented identifying the regulatory sequences required to express the transgene in a stem cell, plant cell, bacterial cell, archaebacterial cell, etc., etc. This is pertinent because the metes and bounds of the claim scope may vary substantially depending upon the host cell at issue (e.g., AAV vectors do not work in plant, bacterial, or archaebacterial cells, but the claim scope encompasses all possible regulatory sequences for use in all possible host cells). Accordingly, claim 11 is rejected as indefinite (see MPEP § 2173.05(b)(II)). For purposes of applying prior art, an AAV2 vector with standard promoters, ITRs, etc. are understood to fully satisfy the requirements of instant claim 11.
Claim 18 refers to “at least 90% identity” (i.e., a sequence comparison) but provides no SEQ ID NOs corresponding to any cited component permitting such a comparison to be made, which renders the claim scope indefinite (see, e.g., MPEP § 2173.05(b)(II), noting that references to an object that is variable may render a claim indefinite). Here, such sequences are understood to vary naturally and normally in the prior art (e.g., SNPs, etc.), wherein such variation alters the pending claim scope in the absence of clear guidance and recitation of an unchanging comparator sequence. Accordingly, claim 18 is rejected as indefinite. For purposes of applying the prior art, the recited structural limitation is presumed fully satisfied by any prior art AAV2 vector.
Claim 19 refers to a “poly-A sequence”, which renders the claim scope indefinite because it is unclear if the term means a polyadenylation signal (e.g., AUUAAA or AAUAAA) or if “poly-A” refers to a poly(A) tail sequence (e.g., A repeating, such as AAAAAA). It is unclear which is meant, which alters the claim scope. Clarification is required. For purposes of applying prior art, it is presumed that a polyadenylation signal is required rather than a pre-formed poly-A tail sequence, which is reasonable because such sequences are typically present in AAV2 vectors.
Claims 2-13, 16-20, and 32 depend directly or indirectly from an indefinite base claim, but fail to rectify the indefiniteness of the base claim. Accordingly, these claims are rejected for the reasons discussed above and applied to the claimed upon which these claims depend.
Claims 1-13, 16-20, and 32 are rejected.
Claim Rejections - 35 USC § 112(a), Written Description
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 1-13, 16-20, and 32 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.
Brief Statement of the Issue(s)
The pending claims recite functional limitations (e.g., instant claims 1, 6, 11), that do not correspond to a clear structure/function relationship, and therefore the claim scope is unknown. The claims may read upon >>trillions of species (e.g., SEQ ID NO: 2 is a 410-mer, and 60% identity means >160 amino acids may be altered, which is >20160 sequences), or perhaps only a dozen or fewer in view of the ill-defined functional limitations. Accordingly, the description does not reasonably convey to an artisan that Applicant was in possession of the full scope of the claimed invention.
Claim Scope
Claims 1, 6, and 11 are representative of the pending claims scope. Issues with these claims have been discussed above under 35 USC 112(b), and those discussions are incorporated into the instant rejection.
Claim 1 may encompass >>trillions of species (i.e., vectors differing by promoters, regulatory elements, etc., and differing by transgene identity because SEQ ID NO: 2 is a 410-mer, and 60% identity means >160 amino acids may be altered, which is >20160 sequences) or perhaps only dozen or less, because claim 1 recites the functional limitation requiring that the species “ha[ve] serine protease inhibition activity and [are] at least partially resistant to oxidative inactivation” (see, e.g., instant claim 1); and instant claim 6 further limits the functional limitation of claim 1 (i.e. instant claim 6 recites “the serine protease inhibition activity comprises inhibition of plasmin, tissue plasminogen activator and/or urokinase plasminogen activator”), but these functional limitation fails to correspond to any structure/function relationship of record commensurate in scope with the instant claim scope.
Accordingly, the functional limitations are understood to merely recite a function that Applicant hopes and desires for the claimed invention to achieve, without actually disclosing or identifying the structural limitations required to achieve such limitations.
Therefore, it is unclear if the claim scope encompass trillions of species or perhaps only a few in view of the functional limitations set forth in the claim(s). Accordingly, the claim scope reasonably appears to be vast and highly varied.
Actual Reduction to Practice
The original disclosure provides a laundry list disclosure encompasses >>trillions of diverse species. However, only two species appear to have been reduced to practice, namely a pSF-CAG-GFP plasmid used to transfect SHSY5Y cells, wherein a mutant neuroserpin with a M363R mutation was reduced to practice (see, e.g., Spec. filed 6/16/2023 at 31 at lines 20-30, Fig. 1A-1D), and the vector AAV2-CAG2-eGFP-T2A-hNS-WPRE (see, e.g., Spec. filed 6/16/2023 at 36-37 at bridging ¶). Accordingly, the only “host cells” used were SHSY5Y cells (i.e., immortalized neuroblastoma cells) and retinal ganglion cells (RGCs).
Zero vectors appropriate for bacterial host cells were reduced to practice.
Zero vectors appropriate for plant cells were reduced to practice.
Zero vectors appropriate for archaebacteria were reduced to practice.
Zero vectors appropriate for fungal cells were reduced to practice.
Zero “mutants” of human neuroserpin, besides instant SEQ ID NO: 2, were reduced to practice and shown to be functional, wherein the mutants differed from human wild-type at any position other than M363 (i.e., SEQ ID NO: 2).
In summary, at best, Applicant appears to have disclosed two vectors encoding a single mutant of human neuroserpin, wherein the single mutant sequence disclosed shares 99.7% identity with wildtype, and differs at a single position (compare instant SEQ ID NO: 2 with US’020 at SEQ ID NO: 2, claims 1-42, showing vectors encoding sequences sharing 409/410 residues, or 99.7% identity, and having a single difference at Met363)
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Therefore, the disclosure appears to reduce to practice of a single species of mutant neuroserpin that differs from wildtype at a single position.
Assessment of whether disclosed species are representative of the claimed genus
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus (see, e.g., MPEP § 2163(II)(3)(a), MPEP §2163.03(V)). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
In this case, the claims ostensibly encompass >>trillions of species, but appear to reduce to practice one mutant of neuroserpin encoded in two types of vectors.
Although the MPEP does not define what constitutes a sufficient number of representative species, the Courts have indicated that the disclosure of two species within a subgenus did not describe that subgenus. In re Gostelli, 872 F.2d at 1012, 10 USPQ2d at 1618. Similarly, the disclosure of one species of mutant neuroserpin and two types of vectors of the claimed invention does not provide sufficient disclosure to satisfy the written description requirement for the instantly claimed genus.
Identifying characteristics of the genus
In the absence of a reduction to practice of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
Here, the functional limitations at issue do not correspond to a structure/function relationship commensurate in scope with the instant claim scope. Rather, the functional limitations of claims 1 and 6 are only utilized as a vague attempt to capture unknown and undisclosed structures, sufficient to achieve the functional result that Applicant hopes and desires that the disclosed invention is able to achieve. However, other than SEQ ID NO: 2, an artisan would be unable to identify, a priori, whether or not a sequence satisfied the functional limitations recited at the instant claims for any sequence having less than 99.7% sequence identity with instant SEQ ID NO: 2.
Although it is reasonably understood that a sequence sharing 60% sequence identity with instant SEQ ID NO: 2, but having an additional >100 methionine residues at residues outside of the reactive loop of neuroserpin would likely not satisfy the functional limitations, it is uncertain. Similarly, because SEQ ID NO: 2 is a 410-mer, at claims 1, 6, and 11 that “60% identity” limitation ostensibly means >160 amino acids may be altered. This means that additional cysteine residues, prolines, arginines, etc. may ostensibly be added at over 150 residues. This raises a substantial and materially question, namely “which of these >>trillions of species are actually functional?”. However, no guidance is provided in the specification, and therefore, an artisan making and using such a vector comprising a sequence sharing 60%, 65%, 70%, etc. sequence identity with instant SEQ ID NO: 2 would not know, a priori, if the vector read upon the instant claims or not, without first making and using (and infringing) upon such claim scope. Notably, the courts have stated that
Regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.” University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1984 (CAFC 2004) (emphasis added).
Accordingly, because it is unclear what compounds do or do not satisfy the functional limitations of the pending claims, and an artisan would be unable to identify infringing from non-infringing compounds, “the inventor cannot lay claim to the subject matter”.
Predictability in the Art
Although the level of skill in the art is high, the predictability in the art is low due to the complexity of biological systems, biochemistry, biophysical interactions and nearest neighbor effects of amino acid substitutions. Specifically, an artisan would not be able to predict or identify, a priori, and in the absence of any guidance or consensus structures exactly what compounds would be capable of satisfying the functional limitations of instant claims 1, 6, and 11.
Accordingly, in the absence of sufficient structure/function teachings identifying particular compounds capable of satisfying the functional limitations of instant claims 1, 6, and 11, as required to practice the full scope of the claims, an artisan would not reasonably conclude that Applicant possessed the full scope of the broad and highly varied claim scope.
Conclusion
The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does "little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). The courts have stated that “merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus” (see, e.g., AbbVie v. Janssen, 111 USPQ2d 1780 (Fed. Cir. 2014) at 1789). In addition, the Courts have stated
“[r]egardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.” University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1984 (CAFC 2004) (emphasis added).
This is pertinent because, in the instant case, Applicants have claimed a broad and highly varied genus comprising an unknown number of species defined by reference to one or more functional limitations; however, the originally filed disclosure has failed to identify any common structure/function relationship sufficient to permit an artisan to identify what structures are included or excluded by the claim scope. This also means that it is prima facie unclear what structures are infringe or do not infringe upon the pending claim scope.
In conclusion, for the reasons discussed above, the skilled artisan would not reasonably conclude that the inventor(s), at the time the application was filed, had possession of the full scope of the claimed invention.
Claims 1-13, 16-20, and 32 are rejected.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-11, 13, 16, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over US6008020 in view of Gupta et al.6 and WO2016069574A1.
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and in preceding rejections, and those interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
Regarding instant claims 1-5, 6, 9-11, 13, 16, 32, and vectors comprising human neuroserpin, US’020 discloses and pertains to human neuroserpin (see, e.g., US’020 at col 1 at lines 1-14, col. 9 at lines 15-20, SEQ ID NO: 2), and recombinant vectors comprising polynucleotides encoding human neuroserpin (see, e.g., US’020 at claims 1-2, 4, 22-23, 26-27, col 42 at line 53 to col. 50 at line 11 discussing Examples 1-3). This is pertinent because human neuroserpin comprises MIAX3SRX1X2VL, wherein X3 is I, X1 is M, and X2 is A (compare instant SEQ ID NO: 2 with US’020 at SEQ ID NO: 2, claims 1-42, showing vectors encoding sequences sharing 409/410 residues, or 99.7% identity, and having a single difference at Met363)
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Regarding claims 1, 6, and “serine proteinase inhibition activity”, such as “inhibition of plasmin”, US’020 refers to human neuroserpin as “BAIT” (see, e.g., US’020 at col. 9 at lines 55-65, col. 10 at lines 2-16), and explicitly shows that human neuroserpin inhibits plasmin, tPA, and uPA (see, e.g., US’020 at Figure 5, col. 13 at lines 10-15). Regarding claims 1, 3, 4, 9-10, and the “reactive centre loop”, US’020 identifies that human neuroserpin has a reactive center loop, which is double-underlined at Figure 2 (see, e.g., US’020 at Fig. 2, col. 12 at lines 40-63, wherein “The putative reactive site (cleaved by a target protease), between Arg at BAIT position 362 and Met at BAIT position 363, is marked” at Figure 2), and the reactive center loop comprises the sequence MIAISRMAVL (compare instant SEQ ID NO: 2 with US’020 at SEQ ID NO: 2, showing identity at all positions except X1, which is Met). Regarding instant claim 11, 13, and a vector comprising a regulatory sequence comprising a promoter permitting expression of human neuroserpin in a host cell, US’020 identifies that human neuroserpin may be contained in a vector (see, e.g., US’020 at claims 1-2, 4, 22-23, 26-27, col 42 at line 53 to col. 50 at line 11 discussing Examples 1-3), and specifically identifies that such vectors may include promoters suitable for use in expressing the protein in host cells (see, e.g., US’020 at col. 21 at line 57 to col. 23 at line 29), including T3, T7, PR, PL, CMV, HSV, SV40 promoters, among others (see, e.g., US’020 at col. 22 at lines 25-40). Regarding instant claims 1, 16, and a viral vector, US’020 identifies that human neuroserpin may be contained in a vector (see, e.g., US’020 at claims 1-2, 4, 22-23, 26-27, col 42 at line 53 to col. 50 at line 11 discussing Examples 1-3), and specifically directs and identifies that viral vectors may be utilized (see, e.g., US’020 at col. 22 at lines 18-27). Regarding instant claims 1, 32, and a pharmaceutical composition comprising the vector, US’020 identifies that human neuroserpin may be contained in a vector (see, e.g., US’020 at claims 1-2, 4, 22-23, 26-27) and exemplifies embodiments wherein such vectors are made and used (see, e.g., US’020 at col 42 at line 53 to col. 50 at line 11 discussing Examples 1-3), wherein such formulations utilized for pharmaceutical assays are understood to be pharmaceutical compositions.
US6008020 differs from the instantly claimed invention as follows: Although US’020 discloses vectors comprising human neuroserpin sharing 409/410 residues (99.7% identity) in common with instant SEQ ID NO: 2, US’020 differs from the instant claims because instant SEQ ID NO:2 comprises a single mutation difference at Met363 (i.e., US’020 teaches a MIAX3SRX1X2VL, wherein X1 is M, rather than something else). Therefore, the relevant issue is whether or not it would have been obvious to one of ordinary skill in the art to modify human neuroserpin by mutating the methionine residue at the reactive center loop.
Human neuroserpin was known in the pharmaceutical arts and had desirable activity: Gupta provides evidence suggesting that human neuroserpin exerts protective effects in neurons (see, e.g., Gupta at 2 at 1st full ¶), identifies that human neuroserpin could be administered to retinal ganglion cells (RGCs) to suppress apoptotic cell death in response to ischemic injury (see, e.g., Gupta at 2 at 1st full ¶), and identifies that human neuroserpin regulates the activity of plasmin (see, e.g., Gupta at title, abs, 1 at 1st full ¶, 2 at 1st to 2nd full ¶¶).
Gupta identifies an art-recognized problem: Gupta identifies that glaucoma was associated with oxidative inactivation of neuroserpin via methionine residues (see, e.g., Gupta at title, abs, 7-8 at bridging ¶, 8-9 at bridging ¶, 10 at § “Discussion”, 13 at 1st full ¶, 14 at 1st partial ¶). Gupta identifies that human neuroserpin undergoes oxidative inactivation in glaucoma patients presumably due to the chronically increased oxidative stress under glaucoma conditions (see, e.g., Gupta at title, abs, 13 at 1st full ¶). The oxidative inactivation of human neuroserpin leads to increased plasmin activity, wherein increased plasmin activity is associated with undesirable outcomes (see, e.g., Gupta at title, abs, 1 at 1st full ¶, 2 at 1st to 2nd full ¶¶, 7-8 at bridging ¶, 9 at final ¶, 10 at § “Discussion”, 13 at 1st full ¶).
Gupta provides an art-recognized solution and direct guidance to make, use, and test oxidatively resistant forms of human neuroserpin: Gupta provides direct guidance and motivation to make, use, and test oxidatively resistant forms of neuroserpin in experimental glaucoma models:
Future phenotype rescue experiments can be carried out in mice models by over-expressing oxidatively resistant form of neuroserpin in the specific retinal neurons. Exposing these animals to experimental glaucoma will highlight the contribution of neuroserpin oxidation in mediating glaucomatous damage to the retina.
(see, e.g., Gupta at 14 at 1st partial ¶, emphasis added)
Accordingly, an artisan would be motivated to make and use oxidatively resistant forms of human neuroserpin, and specifically to make forms capable of being over-expressed in specific retinal neuron cell types.
Gupta provides guidance directly artisans to specifically make, use, and test oxidatively resistant forms of human neuroserpin by specifically modifying the methionine residue in the reactive site loop of human neuroserpin: Gupta identifies that “Neuroserpin contains about twenty met residues, which makes the molecule susceptible to oxidative changes” (see, e.g., Gupta at 13 at 1st full ¶). Although Gupta cautions that “this study demonstrated enhanced met oxidation in neuroserpin in glaucoma and under the oxidising conditions but does not implicate any particular met residue in the process” (see Gupta at 8 at 1st partial ¶; see also id. at 13 at 1st full ¶), Gupta clearly informs artisans that the Met in the reactive site loop would be reasonably predicted and expected to contribute to oxidative inactivation:
Oxidative stress can modify the met residues including the reactive site loop met residue to met sulfoxide, as shown in the case of other serpins such as alpha-1-proteinase inhibitor and potentially decrease the proteinase inhibitory potential of neuroserpin.
(see, e.g., Gupta at 13 at 1st full ¶, emphasis added);
Neuroserpin contains several methionine residues in addition to a conserved reactive site methionine and our study revealed enhanced oxidation of Met residues in the serpin under glaucoma conditions. Met oxidation was associated with loss of neuroserpin inhibitory activity . . .
(see, e.g., Gupta at abs, emphasis added); and
Neuroserpin has an exposed methionine residue on its reactive site loop like many other members of the serpin superfamily. The presence of about 20 other methionines in its amino acid sequence along with a critical met residue at reactive site makes the inhibitor sensitive to oxidative stress induced modification to met sulfoxide.
(see, e.g., Gupta at 7 at final ¶);
Accordingly, although Gupta ostensibly cautions artisans that the proffered experiments could not identify a particular methionine residue responsible for the inactivation of human neuroserpin (see Gupta at 8 at 1st partial ¶; see also id. at 13 at 1st full ¶), one of ordinary skill in the art would readily appreciate that from among “about twenty met residues”, Gupta only specifically references and identifies a single methionine, namely the single methionine in the reactive site loop of human neuroserpin (see, e.g., Gupta at abs, 7 at final ¶, 13 at 1st full ¶)7. Accordingly, an artisan would readily be motivated to make and use oxidatively resistant forms of human neuroserpin, as suggested by Gupta (see, e.g., Gupta at 14 at 1st partial ¶), by specifically forming “oxidatively resistant form of neuroserpin” by specifically modifying the single methionine located at the reactive site loop of human neuroserpin.
The “Met in the reactive site loop” would be readily understood by an artisan to refer to Met363 of SEQ ID NO: 2 of US’020: Notably, an artisans would readily appreciate that the “Met in the reactive site loop” would be Met363 of human neuroserpin (see, e.g., US’020 at Fig. 2, col. 12 at lines 40-63, wherein “The putative reactive site (cleaved by a target protease), between Arg at BAIT position 362 and Met at BAIT position 363, is marked” at Figure 2).
One of ordinary skill in the serpin protein arts would readily know how to make and use oxidatively resistant proteins by mutating methionine residues: WO2016/069574 pertains to serpin proteins and is relevant to serpin mutants (see, e.g., WO’574 at title, abs, passim), including neuroserpin (a.k.a., “SERPINI1”) (see, e.g., WO’574 at ¶[0008]). WO’574 identifies that
Without wishing to be bound by theory, the Met mutation(s) prevent oxidation and subsequent inactivation of the inhibitory activity…
(see, e.g., WO’574 at ¶[00014], emphasis added); and
Oxidation of [a serpin protein] within the reactive site loop at Met351 and or Met358 dampens the ability of [the serpin protein] to inhibit neutrophil elastase. As shown in Figure 1G, oxidative inactivation can be reduced through mutations….
(see, e.g., WO’574 at ¶[000129], emphasis added).
Critically, regarding instant claims 1-5, 7-8, and specific substitutions of the methionine at the active site loop, WO’574 informs artisans that “the Met residue can be substituted with any amino acid”, wherein leucine (Leu, L) and glutamate (Glu, E) are exemplified, and wherein such mutations are expressly taught for use at “the reactive site loop” (see, e.g., WO’574 at ¶[00014], [000129]).
In summary, the only difference between the claimed invention and the prior art vectors encoding human neuroserpin is a single mutation of the methionine residue at the reactive site loop (i.e., position Met363 of SEQ ID NO: 2 of US’020). However, regarding the minor structural difference at issue, a basic threshold issue is simply whether or not an artisan would have reasonably mutated Met362 in SEQ ID NO: 2 of US’020, with a reasonable expectation of success. As explained above, Gupta provides direct guidance and motivation to make, use, and test compounds suitable for over-expressing oxidatively resistant form of neuroserpin in retinal neurons (see, e.g., Gupta at 14 at 1st partial ¶, emphasis added), and reasonably directs artisans to suspect that the single Met in the reactive site loop is suspected of causing oxidative inactivation (see, e.g., Gupta at abs, 7 at final ¶, 13 at 1st full ¶). Therefore, artisans would have readily understood that they could predictably and expectedly create oxidatively resistant form of neuroserpin by mutating the single Met in the reactive site loop of neuroserpin to any other amino acid in view of WO’574, wherein such mutation would yield predicted and expected results, namely a mutant human neuroserpin having an M363X mutation, wherein X is any amino acid other than methionine, and wherein the methionine mutation would be predicted and expected to be an oxidatively resistant form of neuroserpin that would prevent or reduce oxidation and subsequent inactivation of inhibitory activity as taught and suggested by WO’574 and Gupta. Regarding the specific substitutions to R, S, T, F, N, E, K, or D as recited at dependent claims 2, 5, and 7-8, WO’574 identifies that “the Met residue can be substituted with any amino acid” (see, e.g., WO’574 at ¶[00014], [000129]), and therefore, absent objective evidence to the contrary, the nineteen alternative amino acids for this position would be readily understood to be functionally equivalent “non-methionine” residues for the purpose of avoiding methionine oxidation and subsequent inactivation of neuroserpin activity (see, e.g., WO’574 at ¶[00014], [000129]) (see, e.g., MPEP § 2144.06(II); see also MPEP § 2144.07, noting that “The selection of a known material based on its suitability for its intended use supports a determination of prima facie obviousness”; see also Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327 (1945), explaining that "[r]eading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle."). Accordingly, the specific selection of a particular non-methionine amino acid does not weigh in favor of non-obviousness in the absence of evidence of criticality, because all 19 amino acids would be understood to be suitable to avoid oxidation of a methionine residue, and no benefit has been identified on record suggesting one choice is better or less predictable than another.
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s):
First, the claimed invention is the simple substitution of methionine in the reactive site loop of human neuroserpin as taught by US’020 for a non-methionine amino acid as suggested by Gupta and WO’574, wherein such substitution would yield predictable results, namely a vector comprising a mutant human neuroserpin having an M363X mutation, wherein X was any amino acid other than methionine, and wherein the mutant human neuroserpin would be predicted and expected to prevent or reduce oxidation and subsequent inactivation of inhibitory activity relative to normal human neuroserpin as taught and suggested by WO’574 and Gupta (see, e.g., MPEP § 2143(I)(B), (G));
Second, or alternatively, the claimed invention is the obvious application of a known technique of preventing oxidation and subsequent inactivation of inhibitory activity of a serpin (i.e., substitution of a methionine in a reactive site loop of a serpin with a non-methionine residue as taught by WO’574) to improve the serpin of US’020 (i.e., human neuroserpin), wherein such application would predictably result in the improvement of human neuroserpin in the vectors of the primary reference in the same way, namely by reducing or preventing oxidative inactivation reported by Gupta (see, e.g., MPEP § 2143(I)(C), (G));
Third, or alternatively, in view of the explicit guidance of Gupta to make “oxidatively resistant forms of neuroserpin”, an artisan would readily review known techniques for making such oxidatively resistant forms, including replacing methionine residues with non-methionine amino acids as taught and suggested by WO’574, wherein applying such techniques would predictably yield vectors comprising a mutant human neuroserpin having an M363X mutation, wherein X was any amino acid other than methionine, and wherein such mutant human neuroserpin would be predicted and expected to be “oxidatively resistant” to inactivation relative to normal human neuroserpin as taught and suggested by WO’574 and Gupta (see, e.g., MPEP § 2143(I)(D), (G)).
Accordingly, the claimed invention is obvious in view of the prior art.
No evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date. Note that evidence confirming the expectation of the prior art.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, as noted by WO’574, it is well-within the ordinary skill in the art to make and use vectors comprising mutant human neuroserpin proteins comprising a mutation at a methionine in a reactive site.
Accordingly, claims 1-11, 13, 16, and 32 are rejected.
Claims 12-13 and 16-20, are rejected under 35 U.S.C. 103 as being unpatentable over US6008020 in view of Gupta et al.8 and WO2016069574A1 as applied to claims 1-11, 13, 16, and 32 above, and further in view of LeBec et al9. and Chitranshi et al.10.
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and in preceding rejections, and those interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
The teachings of US’020, Gupta, and WO’574 as applied to claims 1-11, 13, 16, and 32, have been discussed in a preceding rejection, and those teachings are incorporated into the instant rejection.
US’020, Gupta, and WO’574 differ from instant claims 12 and 17-20 as follows: Although US’020, Gupta, and WO’574 direct artisans to utilize viral vectors encoding mutant neuroserpin having an M363X mutation, these references do not explicitly teach the specific use of an AAV vector suitable for use in an RGC host cell. However, such differences were well-known in the vector arts as explained below.
LeBec and Chitranshi are cited herein to establish the state of the AAV vector arts. Regarding claims 11, 13, and 16-20, LeBec discloses that AAV vectors “possess many great potential for clinical applications due to their wide range of tissue targets but also their excellent preclinical safety profile” (see, e.g., LeBec at abs). LeBec addresses the rationale design and selection of various regulatory elements to be inserted into AAV expression cassettes (see, e.g., LeBec at abs). Regarding instant claims 11, 13, 16-17, and AAV vectors comprising a promoter such as CAG, LeBec directs artisans to utilize AAV vectors (see, e.g., LeBec at abs), and informs artisans that constitutive promoters such as “hybrid CMV-chicken β-actin” (i.e., CAG, a.k.a. CB or CBA) may be utilized, which is art-recognized as “powerful promoters and are frequently used as ubiquitous ones” (see, e.g., LeBec at 806 at col I at 1st full ¶). Therefore, utilizing a promoter with an AAV vector is routine in the art. Regarding instant claim 11 and the WPRE (woodchuck hepatitis virus post-transcriptional regulatory element) present in the originally elected species, LeBec identifies that incorporation of WPRE was known and considered optional in the design of standard AAV vectors (see, e.g., LeBec at Fig. 1 on 807, 807-808 at bridging ¶). LeBec identifies that WPRE was known to increase expression, but that it was “rather large (600 bp)” and therefore could only be utilized in a “rAAV cassette where the other genetic elements are small” (see, e.g., LeBec at Fig. 1 on 807, 807-808 at bridging ¶). Regarding instant claims 16-20, and AAV2 vectors comprising poly-A sequences and inverted terminal repeats (ITR), LeBec identifies that standard AAV vectors “are flanked by the ITR of serotype 2 at both ends”, and that “The standard rAAV cassette contains either a constitutive promoter or a tissue-specific promoter to drive the transgene expression and a polyA sequence” (see, e.g., LeBec at Fig. 1 on 807), wherein the polyA sequence is present in regulatable vectors at the 3’ end of the transgene (see, e.g., LeBec at Fig. 1 on 807; see esp. id. at Fig. 1(b)), Accordingly, the recitation of a polyA sequence at the 3’ end and the requirement for inverted terminal repeats are understood to merely reflect the standard construction of AAV vectors (see id). Regarding instant claims 11-13, 16-20, and a promoter suitable for expression of a transgene in a retinal ganglion cell (RGC), although LeBec is silent regarding specific AAVs for use in expressing a transgene in RGCs, it is well-within the ordinary skill in the art to simply review prior art AAVs already known and taught in the prior art for such applications. Notably, Chitranshi pertains to glaucoma research, and specifically to the expression of a transgene in retinal ganglion cells (RGCs) using an AAV2 construct (see, e.g., Chitranshi at title, abs), namely AAV2-CAG2-EGFP-T2A-[transgene] (see, e.g., Chitranshi at abs, 437-438 at bridging ¶). Accordingly, one of ordinary skill in the art would readily appreciate that the prior art AAV2 construct could be predictably and expectedly utilized to express a different transgene, such as a neuroserpin, in RGCs. Regarding claim 18, it is understood that AAV2 as taught by Chitranshi (see, e.g., Chitranshi at abs, 437-438 at bridging ¶) and (see, e.g., LeBec at Fig. 1 on 807), would necessarily satisfy the limitation of claim 18 because AAV2 is understood to share 100% identity with itself.
In sum, instant claims 12-13 and 16-20 would be understood by one of ordinary skill in the AAV arts to be routine, and simply substituting one transgene for another transgene in known vector of AAV2-CAG2-EGFP-T2A-[transgene] (see, e.g., Chitranshi at abs, 437-438 at bridging ¶) would be routine in the art, and would readily yield a vector suitable for expressing the transgene in retinal ganglion cells (RGCs). Regarding WPRE, presently unclaimed, WPRE was known in the prior art, art-recognized as an optional, but beneficial element, and could be combined with the Chitranshi so long as the WPRE and transgene, combined, were within the insert size limit of AAV2 (i.e., ~4.7 kb). Therefore, the claims recite known prior art AA2 elements having known functionality, wherein each element merely performs its art-recognized function.
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s): The claimed invention is the combination or simple substitution of prior art elements (i.e., the known vector of AAV2-CAG2-EGFP-T2A-[transgene] as taught by Chitranshi, and the known WPRE element as taught by LeBec); wherein the mutant neuroserpin transgene as suggested in view of US’020, Gupta, and WO’574 is simply substituted in place of the transgene of Chitranshi, wherein such combination or simple substitution would predictably yield the vector of AAV2-CAG2-EGFP-T2A-[neuroserpin mutant], which would predictably and expectedly be able to express the neuroserpin mutant in retinal ganglion cells (RGCs), exactly as suggested in view of LeBec and Chitranshi. (see, e.g., MPEP § 2143(I)(A), (B), (G)). Furthermore, each prior art element of the AAV2 vector would merely perform its art-recognized function in combination as it does separately.
No evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date. Note that evidence confirming the expectation of the prior art.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, as established in view of LeBec and Chitranshi, it was well-within the ordinary skill in the art to make and use AAV2 vectors, such as AAV2-CAG2-EGFP-T2A-[transgene], suitable for use in expressing a transgene in retinal ganglion cells.
Accordingly, claims 12-13 and 16-20 are rejected.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
US 6008020 discloses human neuroserpin (compare instant SEQ ID NO: 2 with US6008,020 at SEQ ID NO: 2, claims 1-42, showing vectors encoding sequences sharing 409/410 residues, or 99.7% identity, and having a single difference at Met363)
US 6191260 discloses human neuroserpin (compare instant SEQ ID NO: 2 with id. at SEQ ID NO: 2 showing vectors encoding sequences sharing 409/410 residues, or 99.7% identity, and having a single difference at Met363).
US 6541452 discloses human neuroserpin (compare instant SEQ ID NO: 2 with id. at SEQ ID NO: 2 showing vectors encoding sequences sharing 409/410 residues, or 99.7% identity, and having a single difference at Met363).
AAG01089.111 is human neuroserpin.
Naso et al.12 pertains to gene therapy approaches using AAV vectors (see, e.g., Naso at title, abs, passim).
Conclusion
No claims are allowed.
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/RANDALL L BEANE/Primary Examiner, Art Unit 1654
1 Products, namely vectors comprising a nucleic acid encoding a sequence at least 60% identical to instant SEQ ID NO: 2, which comprises a reactive center loop comprising MI[IVN]SR[-M][MA]VL, and “has serine protease inhibition activity” and is “at least partially resistant to oxidative inactivation”.
2 e.g., SEQ ID NO: 2 is a 410-mer, and 60% identity means >160 amino acids may be altered, which is >20160 sequences). This genus is functionally limited to just ones that have “serine protease inhibition activity”, but no structure/function teachings is provided identifying which of the >>trillions of potential sequences actually satisfy this functional limitation or not.
3 Le Bec et al., Gene therapy progress and prospects--vectorology: design and production of expression cassettes in AAV vectors. Gene Ther. 2006 May;13(10):805-13. doi: 10.1038/sj.gt.3302724. PMID: 16453010; hereafter “LeBec”.
4 That is, even without considering variability of the vector, the variability of the claimed neuroserpin mutants is vast and highly varied because SEQ ID NO: 2 is a 410-mer, and 60% identity means >160 amino acids may be altered, which is >20160 sequences).
5 That is, even without considering variability of the vector, the variability of the claimed neuroserpin mutants is vast and highly varied because SEQ ID NO: 2 is a 410-mer, and 60% identity means >160 amino acids may be altered, which is >20160 sequences).
6 Gupta et al., Glaucoma is associated with plasmin proteolytic activation mediated through oxidative inactivation of neuroserpin. Sci Rep. 2017 Aug 21;7(1):8412. doi: 10.1038/s41598-017-08688-2. PMID: 28827627; PMCID: PMC5566433; cited in Restriction Requirement mailed 6/22/2026.
7 The Court has clearly explained that "A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." (see KSR, 550 U.S. at 421, 82 USPQ2d at 1397), and that "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle" (see id. at 420, 82 USPQ2d at 1397). Accordingly, Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ" (see, e.g., id. at 418, 82 USPQ2d at 1396).
8 Gupta et al., Glaucoma is associated with plasmin proteolytic activation mediated through oxidative inactivation of neuroserpin. Sci Rep. 2017 Aug 21;7(1):8412. doi: 10.1038/s41598-017-08688-2. PMID: 28827627; PMCID: PMC5566433; cited in Restriction Requirement mailed 6/22/2026.
9 Le Bec et al., Gene therapy progress and prospects--vectorology: design and production of expression cassettes in AAV vectors. Gene Ther. 2006 May;13(10):805-13. doi: 10.1038/sj.gt.3302724. PMID: 16453010; hereafter “LeBec”.
10 Chitranshi et al., Loss of Shp2 Rescues BDNF/TrkB Signaling and Contributes to Improved Retinal Ganglion Cell Neuroprotection. Mol Ther. 2019 Feb 6;27(2):424-441. doi: 10.1016/j.ymthe.2018.09.019. Epub 2018 Oct 4. PMID: 30341011; PMCID: PMC6369445; hereafter “Chitranshi”.
11 GenBank: AAG01089.1, Neuroserpin [Homo sapiens], NCBI Genbank, 10-JUN-2016, attached as 1 page pdf, also available at https://www.ncbi.nlm.nih.gov/protein/AAG01089.1 (last visited 9/25/2026).
12 Naso et al., Adeno-Associated Virus (AAV) as a Vector for Gene Therapy. BioDrugs. 2017 Aug;31(4):317-334. doi: 10.1007/s40259-017-0234-5. PMID: 28669112; PMCID: PMC5548848; hereafter “Naso”.
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