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 1-4, 6-17, 20, and 23-25 are pending. Claims 3 and 11-12 were amended in the Reply to the Requirement. Claims 4, 6-7, 13-16, and 24 are withdrawn as directed to a non-elected species. Claims 1-3, 8-12, 17, 20, 23, and 25 are pending and presently considered.
Power of Attorney Not of Record
A POA has not been filed in the instant case. 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 without traverse of the species of Example 1.10 using a transgene encoding Flag-ZPR1 in the reply filed on 5/12/2026 is acknowledged.
Examiner notes that Applicant mistakenly refers to five different species rather than one (see, e.g., Reply filed 5/12/2026 at 7). Examiner notes the parameters define a single, elected species of the invention rather than five separate species (see, e.g., Requirement mailed 1/12/2026 at 3-5; see esp. id. at 3 at 2nd full ¶).
The single, originally elected species is understood as follows: The species of Example 1.10 pertains to the overexpression of ZPR1 in vivo, which allegedly “rescues DNA damage associated with R-loop accumulation and prevents degeneration of motor neurons in SMA” (see, e.g., Spec. filed 5/22/2023 at ¶¶[00110]-[00113]). The species of method involved SMA mice that were modified to overexpressed Flag-Zpr1 under the control of mouse Rosa26 promoter, wherein such overexpression resulted in neurons that were “healthy and were rescued of axonal defects such as retraction, bending, folding of axons [] compared to neurons from SMA mice” (see, e.g., Spec. filed 5/22/2023 at ¶¶[00110]-[00113]).
Although in the response filed 5/12/2026, Applicant identifies that the transgene encoding Flag-ZPR1 is represented by instant SEQ ID NOs: 1-2, (see, e.g., Reply filed 5/12/2026 at 7), Example 1.10 does not actually identify whether human or mouse ZPR1 was utilized in the transgene, since transgenes may be derived by intraspecies transgenesis (see, e.g., Reply filed 5/12/2026 at 7; Spec. filed 5/22/2023 at ¶¶[00110]-[00113]). This is pertinent because instant SEQ ID NO: 2 is understood to be human ZPR1 (compare instant SEQ ID NO:2 with NP_003895.11 human ZPR1, showing 100% sequence identity; compare instant SEQ ID NO:2 with NP_035882.12 mouse ZPR1, showing 415/459 identities or 90.4% sequence identity). Similarly, instant SEQ ID NO: 1 is understood to be human ZPR1 mRNA (compare instant SEQ ID NO: 1 with NM_003904.53 showing 100% sequence identity). For purposes of examination, any prior art disclosure of a Flag-Zpr1 under the control of mouse Rosa26 promoter is reasonably understood to read upon the originally elected species.
The originally elected species is understood to read upon claims 1-3, 8-12, 15, 17, 20, 23, and 25. However, the originally elected species does not read upon all pending claims. Claim 4 requires “an analog or homolog of ZPR1”, which is understood to exclude actual ZPR14; therefore, claim 4 does not read upon the originally elected species. Claim 6 requires “a derivative of ZPR1”, which is understood to exclude ZPR15; therefore, claim 6 does not read upon the originally elected species. Claim 7 requires GFP, which is not identified as present in the originally elected species; therefore, claim 7 does not read upon the originally elected species. Claims 13-14 requires a “derivative of a nucleotide sequence encoding ZPR1”, such as a derivative encoding GFP; however, a “derivative” is understood to exclude actual ZPR16, and instant SEQ ID NO: 1 does not encode GFP; therefore, claims 13-14 do not read upon the originally elected species. Claim 15 requires specific types of administration into a subject, but the originally elected species is understood utilize “transgenic expression” of a ZPR1 transgene in a transgenic organism; wherein “transgenic expression” is understood to require injection into a pro-nucleus in an F0 generation (see, e.g., Kannan et al7 at 70 at col II at final ¶, explaining that transgenic organisms are made by injection of linearized vector DNA into a pronucleus of a parent organism; see also Kannan at Fig. S1(A), illustrating how transgenic organisms are generated). Accordingly, claim 15 does not read upon the originally elected species. Claim 16 requires a “disorder” that “comprises a disease or disorder caused by at least one mutation in the Senataxin (SETX) gene”; however, the elected species is an SMA model, and no mutation in the Senataxin gene was identified as present, and zero such mutations were identified on record as a cause of SMA, but rather SMA is identified as caused by mutations in the SMN1 gene (see, e.g., Spec. filed 5/22/2023 at ¶¶[0070], [00101]). Therefore, claim 16 does not read upon the originally elected species. Claim 24 requires that the disorder or disease to be treated or prevented is ALS4; but the originally elected species is an SMA treatment model. Therefore, claim 24 does not read upon the originally elected species. In sum, claims 4, 6-7, 13-16, and 24 do not read upon the originally elected species.
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 1-3, 8-12, 15, 17, 20, 23, and 25 are rejected in view of the originally elected species and claims that do not read upon the originally elected species are withdrawn.
Claims 4, 6-7, 13-16, and 24 are 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. Election was made without traverse in the reply filed on 5/12/2026.
Claims 1-3, 8-12, 15, 17, 20, 23, and 25 are presently considered.
Priority
The priority claim to PCT/US2021/060258, as filed 11/22/2021, is acknowledged.
Information Disclosure Statement
The IDS filed 5/22/2023 is acknowledged and presently 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 directed to methods of treating or preventing neurodegenerative diseases or disorders, diseases or disorders caused by at least one mutation in the Senataxin (SETX) gene, a diseases or disorder caused by downregulation of SETX protein levels, or combinations thereof. Claim 1 is representative of the pending claim scope. Applicable claim interpretations are set forth below.
Regarding the preamble of claim 1, per MPEP § 2111.02, “where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation”. Here, the body of claim 1 is understood to recite a structurally complete invention, and therefore the preamble is deemed fully satisfied by prior art that satisfies the steps and structures recited in the body of the claim (see also MPEP § 2111.04(I), noting that “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure”).
“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)).
Claim 1 recites the preamble phrase “treating or preventing a disorder in a subject”, which is understood to include prophylactic treatments and complete cures (see, e.g., Spec. filed 5/22/2023 at ¶¶[0049], [00140]). This language has necessitated rejections under 35 USC § 112(a), below.
The diseases and disorders included or excluded by the language
…wherein the disorder is a neurodegenerative disease or disorder, a disease or disorder caused by at least one mutation in the Senataxin (SETX) gene, a disease or disorder caused by downregulation of SETX protein levels, or combinations thereof…
Is unknown, and this functionally defined genus of diseases and disorders has necessitated rejections under 35 USC § 112(a) and § 112(b), below. For purposes of applying prior art, the pending claims are understood to encompass the treatment of SMA(“spinal muscular atropy”).
The term “subject” is understood to include at least any mammal, consistent with instant claim 25, wherein claim 25 is understood to satisfy 35 USC 112(d), which implies that instant claim 1 broadly encompasses more than mammals.
The references to percent homology directly (e.g., instant claims 3, 11-12) or indirectly (e.g., instant claims 1-2, 8-10, 20-23) in view of the definition of ZPR1 (see, e.g., Spec. filed 5/22/2023 at ¶¶[0026]-[0027]8) have necessitated rejections under 35 USC § 112(a) and § 112(b), below. For purposes of applying prior art, references to ZPR1 is understood to include mouse ZPR1 (NP_035882.19), ZPR1 (NP_003895.110), or another art-recognized and explicitly named “ZPR1”.
At claim 20, the “wherein” clause is understood to merely recite intended and expected results that occur upon the completion of the active method steps recited at claim 1, upon administration or expression of any “ZPR1”. This is reasonable because, per MPEP § 2111.04(I), “Claim scope is not limited by claim language that . . . . does not require steps to be performed, or by claim language that does not limit a claim to a particular structure”, and further states that a “whereby clause” in a claim “is not given weight when it simply expresses the intended result of a process step positively recited”.
At claim 23, the “wherein” clause reciting “wherein the administered or expressed ZPR1 treats or prevents the SMA by decreasing R-loop accumulation” is understood to merely recite intended and expected results that inherently or necessarily occur upon the completion of the active method steps recited at claim 1 and upon administration or expression of any “ZPR1”. This is reasonable because, per MPEP § 2111.04(I), “Claim scope is not limited by claim language that . . . . does not require steps to be performed, or by claim language that does not limit a claim to a particular structure”, and further states that a “whereby clause” in a claim “is not given weight when it simply expresses the intended result of a process step positively recited”.
Additional claim interpretations are discussed below.
Claim Objections
Claim 23 is objected to because of the following informalities:
Claim 23 refers to “The metho2d”, which should be “The method” at line 1.
Appropriate correction is required.
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 1-3, 8-12, 17, 20, 23, and 25 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 attempts to define an unknown subgenus of diseases and disorders using a functional description (i.e., “a disease or disorder caused by at least one mutation in the Senataxin (SETX) gene”, “caused by at downregulation of SETX protein levels”, and “combinations thereof”). “Caused by” either “at least one mutation” or “downregulation of SETX protein levels” constitutes functional language because it describes a featured claim limitation (i.e., actual treatable and preventable diseases and disorders within the claim scope) by what a mutation or (protein downregulation) does rather than by actually enumerating the specific diseases or disorders (see, e.g., MPEP § 2173.05(g)). 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, no discussion of all diseases and disorder that may be “caused” entirely, or in part, by any mutation of the SETX gene (or any level of downregulation of SETX protein levels) is actually provided in the originally filed disclosure. Accordingly, such language attempts to create a genus of diseases and disorders of unknown size and of unknown metes and bounds, by referring to causation, rather than by actually informing artisans of what diseases and disorders may be treated or prevented using the claimed method. This lack of clarity is evident by asking questions such as: “is schizophrenia caused by at least one mutation in the Senataxin (SETX) gene?”, “Is idiopathic pulmonary fibrosis included or excluded by such language?”, “Is Jacobsen Syndrome (missing or deleted portion of chromosome 1111) included or excluded by such language?”. The answer to such questions is simply “it is unclear” if the functionally defined genus encompasses these diseases, or otherwise encompasses hundreds or even thousands of other diseases and disorders. Alternatively, it is possible that this claim language only encompasses four diseases and disorders (e.g., ALS4, AOA2, SMA, and ADSMA) (see, e.g., Spec. filed 5/22/2023 at ¶[0053]). Accordingly, the subgenera of diseases defined by the functionally described diseases and disorders at claim 1 lacks clear metes and bounds because it is unknown what actual diseases and disorders are included or excluded by such language; rather, such language shifts the burden to future artisans to “figure out” what the scope of the instant claims might actually be. This indefiniteness and lack of description prevents complete examination of the pending claim scope, because it is unclear what prior art does or does not read upon the instant claim scope. Accordingly, claim 1 is rejected as indefinite. For purposes of applying prior art, the pending claims are understood to encompass the treatment of SMA. Applicant may overcome this rejection by, for example, amending the claims to replace functional language with an actual recitation of specific diseases and disorders enumerated in the disclosure (e.g., ALS4, AOA2, SMA, and ADSMA).
Claim 1 refers to genus of active components of unknown structures that act as “an enhancer of ZPR1, an analog thereof, a homolog thereof, or combinations thereof”, but it is unclear what the metes and bounds of structures that act as “an enhancer of ZPR1” includes or excludes. The specification provides a tautological definition that provides no guidance: “the enhancer of ZPR1 expression is a compound that enhances the expression of ZPR1” (see, e.g., Spec. filed 5/22/2023 at ¶[0035]). Accordingly, such phrase is functional language because it attempts to capture unknown structures by reciting what the Applicant hopes and wishes for an unknown structure to accomplish. 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 to be achieved by the invention rather than a description of the structures capable of achieving the desired functions, and therefore the claims are indefinite per MPEP § 2173.05(g). This is reasonable 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. From a literal standpoint, food and water act as “an enhancer of ZPR1”, since they are required to prevent death, wherein death would result in the complete cessation of ZPR1 expression, and eating “enhances” the expression of ZPR1 over such levels. This would imply that claim 1 is presumably satisfied by an SMA patient having a meal. Although presumably the claim scope does not include feeding SMA patients food and water, this example illustrates the lack of definiteness of the term “enhancer of ZPR1, an analog thereof, a homolog thereof, or combinations thereof”. 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, here an artisan would be unable to distinguish among structures that do or do not constitute “an enhancer of ZPR1…” as presently claimed, and therefore an artisan would be unable to identify infringing from non-infringing compounds. Therefore, claim 1 is rejected as indefinite.
Claim 1 recites “an analog thereof, a homolog thereof, a derivative thereof, or combinations thereof” of a ZPR1 protein (see, e.g., instant claim 1), but such language lacks clear structural meaning in view of the originally filed disclosure. The source of indefiniteness is that “ZPR1” is ill-defined as any “peptide sequence that shares at least 65% sequence homology to SEQ ID NO: 1” (see, e.g., Spec. filed 5/22/2023 at ¶¶[0026]-[0027]12); “ZPR1 analogs” are subsequently defined as compounds that are “at least 65% identical” to any of the ZPR1 peptides that “shares at least 65% sequence homology to SEQ ID NO: 1” (see, e.g., Spec. filed 5/22/2023 at ¶¶[0026]-[0027], [0030]). Likewise, “ZPR1 derivatives” are subsequently defined as compounds that are derivatives of any of the ZPR1 peptides that “shares at least 65% sequence homology to SEQ ID NO: 1” (see, e.g., Spec. filed 5/22/2023 at ¶¶[0026]-[0029], [0042]). Accordingly, all definitions depend upon what structures constitute “ZPR1” and what structures “shares at least 65% sequence homology to SEQ ID NO: 1”. However, percent homology lacks any clear meaning in the prior art. While the reference to “65% sequence homology” in the definition of ZPR1 is presumably used to mean either “sequence similarity”, or “sequence identity”, the accepted meaning of “homology” is distinct from “sequence similarity” or “sequence identity”, and therefore references to “% homology” are not scientifically meaningful in the prior art, because references to percent homology do not have a set meaning. For example, the prior art of Koonin et al.13 notes that “homology” implies a common evolutionary origin (see, e.g., Koonin at § 2.1.1 at page 1), and further states that
A conclusion that two (or more) genes or proteins are homologous is a conjecture, not an experimental fact. We would be able to know for a fact that genes are homologous only if we could directly explore their common ancestor and all intermediate forms . . . .
. . . .
Even when one comes up with a figure—say, two protein sequences have 10% identical residues and additional 8% similar amino acid residues (a total of 18% similarity)—does this imply homology or not? The only reasonable answer is: it depends. . . .
. . . .
…an alignment of non-homologous sequences is inherently meaningless and potentially misleading. Even if such an alignment attains a relatively high percentage of identity or similarity, no conclusions at all can be inferred from the (spurious, in this case) correspondence between aligned residues. This is why phrases like “significant homology” or “percent homology” are so ludicrous. Homology is a qualitative notion of common ancestry. As long as homology is established, 10% identical residues between two protein sequences could be highly meaningful and amenable to functional interpretation. In contrast, even 30% identity between two sequences that are not homologous in reality could be totally misleading.
(see, e.g., Koonin at § 2.1.1 at pages 1-3, emphasis added).
Notably, Koonin opines that
“the term ‘homology’ is used basically as a glorified substitute for ‘sequence (or structural) similarity’”
(see, e.g., Koonin at § 2.1.1 at pages 1 at 3rd full ¶; emphasis added).
However, although Webber et al14. agrees with Koonin that sequence similarity is “[d]efinitely not” the same as sequence homology (see, e.g., Webber at R332 at col II-III at bridging ¶), Webber opines that
Research papers sometimes wrongly quote values of ‘percent homology’. In these cases ‘percent identity’ is meant, as two genes either have a common ancestor or they do not.
(see, e.g., Webber at R332 at col II-III at bridging ¶, emphasis added).
Therefore, although Koonin and Webber both agree that “sequence homology” is not the same as sequence identity or sequence similarity, both documents present different presumptions about the presumed meaning implied by researchers (i.e., whether or not the term should imply “sequence similarity” or “sequence identity”) (see, e.g., Koonin at § 2.1.1 at pages 1 at 3rd full ¶; see also Webber at R332 at col II-III at bridging ¶). This difference in preferred interpretation between Koonin and Webber is informative of the overall confusing nature of references to “% homology” or “% homologous” because “sequence similarity” and “sequence identity” are not equivalent or synonymous terms as explained by the prior art of Rost15. Rost identifies that proteins can be completely homologous while sharing less than 10% sequence identity (see, e.g., Rost at 85 at col I-II at bridging ¶; see also id. at abs). Rost specifically identifies that the terms “sequence identity”, “sequence similarity”, and “sequence homology” are not synonymous and have distinct, art-recognized definitions (see, e.g., Rost at 85 at col II at 1st full ¶, defining sequence identity; Rost at 86 at col II at § “Definition of sequence identity and sequence similarity”; Rost at 85 at abs, col I at § Introduction, identifying homology is not equivalent to identity). It is therefore clear in the art that references to percent homology as used to define ZPR1 proteins, peptides, analogs, homologs, and derivatives as recited at instant claim 1 is an indefinite, misused, and confusing term in the art that is not synonymous nor equivalent in scope to either “sequence identity” or “sequence similarity”, because “homologous” only implies the existence of a common evolutionary ancestor. Therefore, in the complete absence of a definition, it is unclear if Applicant means for references to percent homology” to imply
(a) percent “sequence identity”;
(b) percent “sequence similarity”;
(c) the existence of homology (i.e., a common ancestor); or
(d) something else entirely.
The correct interpretation substantially and materially alters the pending claim scope because two sequences may share 95% sequence similarity but share 0% sequence identity, and still presumably be homologous. However, two sequences may share 35% sequence identity but not be homologous at all. Per MPEP § 2173.02(II), if the language of the claim is such that a person of ordinary skill in the art could not interpret the metes and bounds of the claim so as to understand how to avoid infringement, a rejection of the claim under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph, is appropriate. Accordingly, because the correct interpretation of the metes and bounds of “an analog thereof, a homolog thereof, a derivative thereof, or combinations thereof” of a ZPR1 protein requires an interpretation of “percent homology”, which lacks any meaningful definition on record or in the prior art, then the metes and bounds of such terms are indefinite. For purposes of applying prior art, the pending claims are understood to encompass the treatment of SMA using a transgene corresponding to instant SEQ ID NO: 1 and encoding SEQ ID NO: 2.
Claim 2 recites the phrase “comprises ZPR1”, but the structure of “ZPR1” is unknown because ZPR1” is ill-defined: “ZPR1 includes a peptide sequence that shares at least 65% sequence homology to SEQ ID NO: 1” (see, e.g., Spec. filed 5/22/2023 at ¶¶[0026]-[0027]16). Accordingly, as discussed above in view of Koonin, Webber, and Rost, above (see discussion above, incorporated herein), the meaning of references to percent homology lacks any clear meaning in the prior art, and therefore reference to “ZPR1” at instant claim 2 is ambiguous because the term “ZPR1” at claim 2 incorporates the definition of “ZPR1” by reference, and the definition is indefinite as explained above. For purposes of applying prior art, “ZPR1” is understood to include instant SEQ ID NO: 2.
Claim 3 recites the phrase “wherein ZPR1 is represented by …. a peptide sequence sharing at least 65% sequence homology to SEQ ID NO: 2”. Accordingly, as discussed above in view of Koonin, Webber, and Rost, above, the meaning of references to percent homology lacks any clear meaning in the prior art (see discussion above, incorporated herein). Therefore, instant claim 3 is ambiguous because references to percent sequence homology lack any clear meaning in the prior art, and sequence homology is not synonymous or equivalent to percent sequence identity or percent sequence similarity. For purposes of applying prior art, “ZPR1” is understood to include instant SEQ ID NO: 2.
Claims 8-10 depend from claim 8, which recites “wherein the active component comprises a nucleotide sequence encoding ZPR1”, which is indefinite because the definition of “ZPR1” is indefinite as it depends upon the meaning of percent homology (see discussion above regarding percent homology and the references of Koonin, Webber, and Rost; those discussions are incorporated into the instant rejection). Therefore, instant claims 8-10 are ambiguous because the definition of ZPR1 is indefinite since the term is defined in a manner lacking clear metes and bounds in view of the prior art, since sequence homology is not synonymous or equivalent to either percent sequence identity or percent sequence similarity. For purposes of applying prior art, “ZPR1” is understood to include instant SEQ ID NO: 2, and claims 8-10 are understood to read upon SEQ ID NO: 1 or the equivalent RNA.
Claims 11-12 attempt to define a nucleotide sequence by reference to sequences “sharing at least 65% sequence homology to SEQ ID NO:1”. The reference to percent sequence homology renders the claim scope indefinite for the reasons discussed above in view of Koonin, Webber, and Rost (see discussion above regarding percent homology and the references of Koonin, Webber, and Rost; those discussions are incorporated into the instant rejection). Therefore, instant claims 11-12 are indefinite because references to percent sequence homology lack any clear meaning in the prior art, and sequence homology is not synonymous or equivalent to percent sequence identity or percent sequence similarity. For purposes of applying prior art, “ZPR1” is understood to include instant SEQ ID NO: 2, and claims 8-12 are understood to read upon SEQ ID NO: 1 or the equivalent RNA.
Claim 25 recites “the subject” (singular) “is selected from the group consisting of a mammal, a human being, or combinations thereof” (see, e.g., claim 25 at lines 1-2). The phrase “or combinations thereof” covers an unknown scope, as it appears to encompass non-existent creatures (e.g., a centaur, a minotaur, etc.) or human-animal hybrids that are not described or enabled in the prior art. Accordingly, the metes and bounds of “or combinations thereof” in this context is indefinite. For purposes of applying prior art, claim 25 is understood to as limiting “subject” to mammals: “wherein the subject is a mammal, optionally a human being”.
Claims 2-3, 8-12, 17, 20, 23, and 25 depend directly or indirectly from an indefinite base claim, but fail to clarify or reconcile the indefiniteness of the base claim. Accordingly, these claims are rejected as indefinite for the reasons applied to the claim(s) upon which they depend.
Claims 1-3, 8-12, 17, 20, 23, and 25 are rejected as indefinite.
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 1-3, 8-12, 17, 20, 23, and 25 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 directly or indirectly attempt to define the claimed invention by utilizing functional language to define both the structures administered (or expressed) and also diseases and disorders to be treated. Such functional language is ill-defined and ill-described, such that an artisan would not reasonable conclude Applicant possessed the full-scope of the invention because the full-scope is not discernable in view of the limited guidance provided.
Claim Scope
Claims 1, 3, and 11-12 are representative of the pending claims scope. These claims illustrate the relevant issues for the instant rejection.
Diseases and disorders: Claim 1 attempts to define an unknown genus of potentially thousands of different diseases and disorders, or perhaps only four diseases and disorders, by referencing causation:
…wherein the disorder is a neurodegenerative disease or disorder, a disease or disorder caused by at least one mutation in the Senataxin (SETX) gene, a disease or disorder caused by downregulation of SETX protein levels, or combinations thereof…
Although presumably the diseases and disorders encompassed by the pending claims include at least ALS4, AOA2, SMA, and ADSMA (see instant claim 17), it is prima facie unknown what other diseases and disorders are included or excluded by such language.
“ZPR1” structures: The ZPR1 proteins or nucleotides encoding ZPR1 protein, and the analogs, homologs, derivatives, “or combinations thereof” refer to unknown structures. More specifically, the claims reference percent homology directly (e.g., instant claims 3, 11-12) or indirectly (e.g., instant claims 1-2, 8-10, 20-23) because “ZPR1” is defined using references to percent homology (see, e.g., Spec. filed 5/22/2023 at ¶¶[0026]-[0027]17). As discussed above under 35 USC 112(b) (incorporated herein), and further discussed below, references to percent homology have no scientific meaning in the prior art, and no explanation of the meaning has been placed on record. Therefore, although it is clear that ZPR1 includes SEQ ID NOs: 1-2, it is prima facie unclear what other structures Applicant is attempting to redefine as “ZPR1” proteins or nucleotides.
“Enhancer of expression of ZPR1, an analog thereof, a homolog thereof, or combinations thereof” structures: The specification provides a tautological definition that provides no guidance: “the enhancer of ZPR1 expression is a compound that enhances the expression of ZPR1” (see, e.g., Spec. filed 5/22/2023 at ¶[0035]). Accordingly, it is unclear what structures Applicant is attempting to claim using such terminology.
“Preventing” diseases: The pending claims explicitly recite preventing any possible “neurodegenerative disease or disorder”. Notably, this includes prevention of Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis (ALS), Huntington's Disease, Frontotemporal Dementia (FTD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA), Prion Diseases (e.g., Creutzfeldt-Jakob Disease), and other diseases recognized in the art as not preventable or curable circa the filing date of the instant Application.
Additional issues have and claim interpretations have been set forth above under 35 USC § 112(b), and those discussions are incorporated into the instant rejection.
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
Applicant provides one examples of a method wherein SMA was treated in SMA mice that were modified to overexpressed a Flag-Zpr1 transgene under the control of a mouse Rosa26 promoter (see, e.g., Spec. filed 5/22/2023 at ¶¶[00110]-[00113]).
Zero examples of in vivo treatment of a subject being administered a ZPR1 “analog”, “homolog”, or “derivative”, or otherwise an “enhancer of expression of ZPR1, an analog thereof, a homolog thereof, or combinations thereof” via an administration route such as “intravenous administration, subcutaneous administration, transdermal administration, topical administration, intraarterial administration, intrathecal administration, intracranial administration, intraperitoneal administration, intraspinal administration, intranasal administration, intraocular administration, oral administration, or combinations thereof” were reduced to practice.
Zero examples of a subject having a disease prevented, other than SMA using a transgene approach, were reduced to practice.
Zero examples of methods evidencing the ability to prevent Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis (ALS), Huntington's Disease, Frontotemporal Dementia (FTD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA), Prion Diseases (e.g., Creutzfeldt-Jakob Disease), and other diseases recognized in the art as not preventable or curable circa the filing date of the instant Application, were reduced to practice.
Zero examples of any working, functional methods of treating any diseases using any compounds lacking 100% sequence identity to SEQ ID NO: 1 or 2 were reduced to practice (i.e., no homologs or homologous sequences were tested and shown to be functional).
In sum, a single species of method reading upon the instant claim scope was actually reduced to practice, but it was substantially limited in scope to a transgenic approach wherein SMA mice that were modified to overexpressed a Flag-Zpr1 transgene under the control of a mouse Rosa26 promoter (see, e.g., Spec. filed 5/22/2023 at ¶¶[00110]-[00113]).
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 encompass an essentially infinite number of methods, wherein unknown and unspecified diseases and disorders are treated or prevented by administering (via any possible route of administration) compounds lacking any common consensus structure (e.g., proteins, DNA, RNA, or “enhancers” presumably including small molecules) at unknown concentrations, dosing frequencies, and dosing regimens. Therefore, there is substantial and high variation within the pending claim scope.
However, as noted above, a single species of method was reduced to practice in a subject (see, e.g., Spec. filed 5/22/2023 at ¶¶[00110]-[00113]). 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 the claimed invention does not provide sufficient disclosure to satisfy the written description requirement for the instantly claimed genus.
Similarly, the disclosure of (i) zero species of in vivo treatment of a subject being administered a ZPR1 “analog”, “homolog”, or “derivative”, or otherwise an “enhancer of expression of ZPR1, an analog thereof, a homolog thereof, or combinations thereof” via an administration route such as “intravenous administration, subcutaneous administration, transdermal administration, topical administration, intraarterial administration, intrathecal administration, intracranial administration, intraperitoneal administration, intraspinal administration, intranasal administration, intraocular administration, oral administration, or combinations thereof”; (ii) Zero examples of a subject having a disease prevented, other than SMA using a transgene approach; (iii) Zero examples of methods evidencing the ability to prevent Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis (ALS), Huntington's Disease, Frontotemporal Dementia (FTD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA), Prion Diseases (e.g., Creutzfeldt-Jakob Disease), and other diseases recognized in the art as not preventable or curable circa the filing date of the instant Application; and (iv) Zero examples of any working, functional methods of treating any diseases using any compounds lacking 100% sequence identity to SEQ ID NO: 1 or 2 were reduced to practice (i.e., no homologs or homologous sequences were tested and shown to be functional) 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.
Diseases and disorders: Claim 1 uses functional language referencing causation in an attempt to define a genus of potentially thousands of different diseases and disorders, or perhaps only four diseases and disorders:
…wherein the disorder is a neurodegenerative disease or disorder, a disease or disorder caused by at least one mutation in the Senataxin (SETX) gene, a disease or disorder caused by downregulation of SETX protein levels, or combinations thereof…
Although presumably the diseases and disorders encompassed by the pending claims include at least ALS4, AOA2, SMA, and ADSMA (see instant claim 17), it is prima facie unknown what other diseases and disorders are included or excluded by such language. Here, no discussion of all diseases and disorders “caused” entirely, or in part, by any mutation of the SETX gene (or any level of downregulation of SETX protein levels) is actually provided in the originally filed disclosure. Accordingly, such language attempts to draw a fence around an unknown number diseases and disorders, but fails to meaningfully inform artisans of what exact diseases and disorders are included or excluded from such limitations. This lack of clarity is evident by asking questions such as: “is schizophrenia caused by at least one mutation in the Senataxin (SETX) gene?”, “Is idiopathic pulmonary fibrosis included or excluded by such language?”, “Is Jacobsen Syndrome (missing or deleted portion of chromosome 1118) included or excluded by such language?”. The answer to such questions is simply “it is unknown in view of the disclosure and prior art”. Therefore, such language does "little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate"19, because it amounts to “merely drawing a fence around a perceived genus”, but the courts have held 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).
“ZPR1” structures: The ZPR1 proteins or nucleotides encoding ZPR1 protein, and the analogs, homologs, derivatives, “or combinations thereof” refer to unknown structures. More specifically, the claims reference percent homology directly (e.g., instant claims 3, 11-12) or indirectly (e.g., instant claims 1-2, 8-10, 20-23) because “ZPR1” is defined using references to percent homology (see, e.g., Spec. filed 5/22/2023 at ¶¶[0026]-[0027]20). More specifically, “ZPR1” is ill-defined as any “peptide sequence that shares at least 65% sequence homology to SEQ ID NO: 1” (see, e.g., Spec. filed 5/22/2023 at ¶¶[0026]-[0027]); “ZPR1 analogs” are subsequently defined as compounds that are “at least 65% identical” to any of the ZPR1 peptides that “shares at least 65% sequence homology to SEQ ID NO: 1” (see, e.g., Spec. filed 5/22/2023 at ¶¶[0026]-[0027], [0030]). Likewise, “ZPR1 derivatives” are subsequently defined as compounds that are derivatives of any of the ZPR1 peptides that “shares at least 65% sequence homology to SEQ ID NO: 1” (see, e.g., Spec. filed 5/22/2023 at ¶¶[0026]-[0029], [0042]). Accordingly, all definitions depend upon what structures constitute “ZPR1” and what structures “shares at least 65% sequence homology to SEQ ID NO: 1”. However, percent homology lacks any clear meaning in the prior art. While the reference to “65% sequence homology” in the definition of ZPR1 is presumably used to mean either “sequence similarity”, or “sequence identity”, the accepted meaning of “homology” is distinct from “sequence similarity” or “sequence identity”, and therefore references to “% homology” are not scientifically meaningful in the prior art, because references to percent homology do not have a set meaning. For example, the prior art of Koonin et al.21 notes that “homology” implies a common evolutionary origin (see, e.g., Koonin at § 2.1.1 at page 1), and further states that
A conclusion that two (or more) genes or proteins are homologous is a conjecture, not an experimental fact. We would be able to know for a fact that genes are homologous only if we could directly explore their common ancestor and all intermediate forms . . . .
. . . .
Even when one comes up with a figure—say, two protein sequences have 10% identical residues and additional 8% similar amino acid residues (a total of 18% similarity)—does this imply homology or not? The only reasonable answer is: it depends. . . .
. . . .
…an alignment of non-homologous sequences is inherently meaningless and potentially misleading. Even if such an alignment attains a relatively high percentage of identity or similarity, no conclusions at all can be inferred from the (spurious, in this case) correspondence between aligned residues. This is why phrases like “significant homology” or “percent homology” are so ludicrous. Homology is a qualitative notion of common ancestry. As long as homology is established, 10% identical residues between two protein sequences could be highly meaningful and amenable to functional interpretation. In contrast, even 30% identity between two sequences that are not homologous in reality could be totally misleading.
(see, e.g., Koonin at § 2.1.1 at pages 1-3, emphasis added).
Notably, Koonin opines that
“the term ‘homology’ is used basically as a glorified substitute for ‘sequence (or structural) similarity’”
(see, e.g., Koonin at § 2.1.1 at pages 1 at 3rd full ¶; emphasis added).
However, although Webber et al22. agrees with Koonin that sequence similarity is “[d]efinitely not” the same as sequence homology (see, e.g., Webber at R332 at col II-III at bridging ¶), Webber opines that
Research papers sometimes wrongly quote values of ‘percent homology’. In these cases ‘percent identity’ is meant, as two genes either have a common ancestor or they do not.
(see, e.g., Webber at R332 at col II-III at bridging ¶, emphasis added).
Therefore, although Koonin and Webber both agree that “sequence homology” is not the same as sequence identity or sequence similarity, both documents present different presumptions about the presumed meaning implied by researchers (i.e., whether or not the term should imply “sequence similarity” or “sequence identity”) (see, e.g., Koonin at § 2.1.1 at pages 1 at 3rd full ¶; see also Webber at R332 at col II-III at bridging ¶). This difference in preferred interpretation between Koonin and Webber is informative of the overall confusing nature of references to “% homology” or “% homologous” because “sequence similarity” and “sequence identity” are not equivalent or synonymous terms as explained by the prior art of Rost23. Rost identifies that proteins can be completely homologous while sharing less than 10% sequence identity (see, e.g., Rost at 85 at col I-II at bridging ¶; see also id. at abs). Rost specifically identifies that the terms “sequence identity”, “sequence similarity”, and “sequence homology” are not synonymous and have distinct, art-recognized definitions (see, e.g., Rost at 85 at col II at 1st full ¶, defining sequence identity; Rost at 86 at col II at § “Definition of sequence identity and sequence similarity”; Rost at 85 at abs, col I at § Introduction, identifying homology is not equivalent to identity). It is therefore clear in the art that references to percent homology as used to define ZPR1 proteins, peptides, analogs, homologs, and derivatives as recited at instant claim 1 is an indefinite, misused, and confusing term in the art that is not synonymous nor equivalent in scope to either “sequence identity” or “sequence similarity”, because “homologous” only implies the existence of a common evolutionary ancestor. Therefore, in the complete absence of a definition, it is unclear if Applicant means for references to percent homology” to imply
(a) percent “sequence identity”;
(b) percent “sequence similarity”;
(c) the existence of homology (i.e., a common ancestor); or
(d) something else entirely.
The correct interpretation substantially and materially alters the pending claim scope because two sequences may share 95% sequence similarity but share 0% sequence identity, and still presumably be homologous. However, two sequences may share 35% sequence identity but not be homologous at all. Accordingly, such unscientific language fails to reasonably describe or permit artisans to identify structures that do or do not satisfy the descriptions set forth on record other than instant SEQ ID NOs: 1 and 2. This is pertinent because 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).
Therefore, in view of zero variability of structure shown or reduced to practice in a method as claimed, and in view of indefinite language regarding “percent homology”, an artisan would be unable to reasonable identify what other structures did or did not constitute “ZPR1” other than instant SEQ ID NOs: 1-2, such that they could avoid infringement. Therefore, “the inventor cannot lay claim to the subject matter”.
“Enhancer of expression of ZPR1, an analog thereof, a homolog thereof, or combinations thereof” structures: The specification provides a tautological definition that provides no guidance: “the enhancer of ZPR1 expression is a compound that enhances the expression of ZPR1” (see, e.g., Spec. filed 5/22/2023 at ¶[0035]). Accordingly, such phrases amount to functional language attempting to draw a fence around an unknown genus of structures that Applicant hopes and desires to claim without actually informing artisans of what structures do or do not constitute such “enhancers”. If interpreted literally, the language may include proteins, peptides, siRNAs, agRNAs, carbohydrates, small molecules, etc., etc, In fact, from a literal standpoint, food and water act as “an enhancer of ZPR1”, since they are required to prevent death, wherein death would result in the complete cessation of ZPR1 expression, and therefore eating food and drinking water to live necessarily and inherently “enhances” the expression of ZPR1. Therefore, it is unclear if prior art teaching SMA patients simply having a meal or a beverage satisfies the requirements of the pending claims or now. Although presumably the claim scope was not intended to include SMA patients merely eating and drinking, this example illustrates the lack of clear meaning and definition of such terms. 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, in the absence of any structural guidance of compounds that do or do not act as “enhancers” or analogs, homologs, or combinations thereof, an artisan would be unable to distinguish among structures that do or do not constitute “an enhancer of ZPR1…” as presently claimed, and therefore an artisan would be unable to identify infringing from non-infringing compounds. Therefore, “the inventor cannot lay claim to the subject matter”.
“Preventing” and “treating” diseases: The pending claims explicitly recite preventing any possible “neurodegenerative disease or disorder”. Notably, this includes prevention of Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis (ALS), Huntington's Disease, Frontotemporal Dementia (FTD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA), Prion Diseases (e.g., Creutzfeldt-Jakob Disease), and other diseases recognized in the art as not preventable or curable circa the filing date of the instant Application. The disclosure provides zero evidence that such diseases could be prevented; furthermore, it is unclear how such diseases would be meaningfully “treated” by overexpressing ZPR1 as presently claimed, and no meaningful discussion of how ZPR1 levels relate to such diseases is provided on record. Accordingly, Applicant clearly does not “possess” such subject matter that was not meaningfully described or mechanistically explained as relevant to all possible neurodegenerative diseases.
Accordingly, the functional limitations and ill-defined functional descriptions of the pending claims is only utilized as a vague attempt to capture unknown and undisclosed structures and treatments sufficient to achieve some functional result that Applicant hopes and desires that the disclosed invention is able to achieve. However, the disclosure but does not meaningfully disclose an unambiguous structure/function relationship permitting an artisan to identify, a priori, which exact structures do or do not satisfy the functional limitations at issue, or even what exact diseases and disorders are preventable or treatable using the claimed steps.
Accordingly, basic identifying characteristics pertinent to the claimed genus are left unanswered.
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, disease and disorder progression, and also disease and disorder causation and pathologies. 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 preventing or treating diseases upon administration at unknown concentrations as presently claimed.
Accordingly, 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 and functionally defined diseases and disorders; however, the originally filed disclosure has failed to identify any common structure/function relationship sufficient to permit an artisan to identify what structures, diseases, and disorders 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.
Claim Rejections - 35 USC § 112(a), Scope of Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3, 8-12, 20, and 25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating SMA by expressing SEQ ID NO:2 via a transgene encoding SEQ ID NO: 1, does not reasonably provide enablement to prevent of all possible neurodegenerative diseases or disorders, all possible diseases or disorders caused by at least one mutation in the Senataxin (SETX) gene, or all possible diseases or disorder caused by downregulation of SETX protein levels, or “combinations thereof”. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
The applicable legal standards for enablement are discussed at MPEP § 2164 and the specific legal standards relevant to determinations regarding the scope of enablement are set forth at MPEP § 2164.08. MPEP § 2164 identifies the following relevant factors for determining “undue” experimentation: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.” The factors which have led the Examiner to conclude that the specification fails to teach how to make and/or use the claimed invention without undue experimentation, are addressed in detail below.
The breadth of the claims and nature of the invention: Claims 1-3, 8-12, 15, 17, 20, 23, and 25 are directed to broad methods of “treating and preventing” any and all types of neurodegenerative diseases and disorders, by administering unknown structures via unspecified routes at unspecified dosages and dosage frequencies (see, e.g., instant claim 1). The pending claim scope has been discussed at length above under 35 USC §112(a), written description, and §112(b), and those discussions are incorporated herein.
Brief introduction of the issue: The enablement provided is not commensurate in scope with the claims because an artisan cannot reasonably prevent diseases recognized in the art as unpreventable.
The amount of direction or guidance presented and the existence of working examples: The originally filed disclosure discloses zero guidance regarding the prevention of any disease other than SMA in a mouse model of SMA using a transgene has been disclosed on record. Accordingly, zero guidance regarding preventing Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis (ALS), Huntington's Disease, Frontotemporal Dementia (FTD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA), Prion Diseases (e.g., Creutzfeldt-Jakob Disease), or other diseases recognized in the art as not preventable or curable circa the filing date of the instant Application, has been placed on record.
The state of prior art: The lack of guidance and working examples is pertinent because the prior art teaches that the causation of some diseases are unknown and the prior art teaches that other diseases cannot be prevented or cured, including Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis (ALS), Huntington's Disease, Frontotemporal Dementia (FTD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA), Prion Diseases (e.g., Creutzfeldt-Jakob Disease). These are not exhaustive examples. However, allegations that an artisan has discovered a means of curing or preventing such diseases, made in the complete absence of any supporting evidence, would be met with skepticism by artisans.
Relative skill of those in the art, and the predictability or unpredictability of the art: Although the relative skill in the art is high, the general predictability of the art regarding the complete prevention of neurodegenerative diseases and disorders is very low due to the complexity of biological systems, biochemistry, disease and disorder progression, and also disease and disorder causation and pathologies, as well as high variability of subject parameters (e.g., age, weight, gender, and state of health), route of administration, dosage, therapeutic windows, etc. Allegations that an artisan had discovered a means of curing or preventing diseases generally recognized as not preventable, made in the complete absence of any objective supporting evidence, would be met with skepticism by artisans.
The quantity of experimentation required to practice the claimed invention based on the teachings of the specification. To utilize the claimed invention commensurate in scope with the pending claim scope, an artisan would be unduly burdened to actually perform all routine clinical and pre-clinical testing on all diseases and disorders (i.e., >>potentially thousands, including Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis (ALS), Huntington's Disease, Frontotemporal Dementia (FTD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA), Prion Diseases (e.g., Creutzfeldt-Jakob Disease), or other diseases recognized in the art as not preventable or curable circa the filing date of the instant Application) using all compounds presently claimed (i.e., infinite number of unknown structures, homologs, analogs, derivatives, and combinations thereof), via all routes of administration and pharmaceutical formulations, as well as a range of dosages, to discover whether or not the claimed invention worked or if it did not work. No credible disclosure of guidance commensurate in scope with such clinical and pre-clinical testing appears on the instant record, and there is no evidence that any art-recognized unpreventable neurodegenerative disease could actually be prevented; therefore any such evidence would amount to a novel discovery.
Conclusion: Therefore, in view of the lack of guidance and lack of working examples showing prevention of diseases, high degree of unpredictability, and failure to address the concerns present in the art, an artisan would be unduly burdened with experimentation in order to practice the full scope of the instantly claimed invention.
Accordingly, claims 1-3, 8-12, 20, and 25 are rejected.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 8-12, 17, 20, 23, and 25 are rejected under 35 U.S.C. 102(a)(2) as being clearly anticipated by Kannan et al24 as evidenced by NP_035882.125 and as evidenced by NM_011752.226.
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and those interpretations are incorporated into the instant rejection. “SMA” is understood to be “spinal muscular atrophy”. Additional claim interpretations are set forth below.
The prior art appears to teach the originally elected species. Regarding instant claims 1-3, 8-12, 17, 20, 23, and 25, Kannan discloses a method of treating SMA by systemically overexpressing ZPR1 in mice via a Flag-mZPR1 transgene, which increases “SMN levels and rescues severe to moderate disease in SMA mice” by preventing accumulation of co-transcriptional R-loops and DNA damage (see, e.g., Kannan at title, abs, 70 at col II at § “Materials and methods” to 71 at col I at §§ “Generation of SMA mice with ZPR1 overexpression (Z-SMA)”, 73 at col I-II at § “Results”, Fig. 1 on 74-75, Fig. 2 on 76-77, Fig. 3 on 78, Fig. 4 on 80-81, Fig. 5 on 82-83, 88 at col I-II at § “Discussion”, 89 at Fig. 8 showing a graphical representation of the mechanism of ZPR1-dependent rescue of spinal muscular atrophy, 91-92 at bridging ¶, 92 at col I at 1st full ¶, Supp. Fig. 1A-E reproduced in part below):
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Regarding instant claims 1-2, 17, 20, 23, 25, and the treatment of a neurodegenerative diseases or disorder of SMA, Kannan explicitly reduces to practice a method of treating “spinal muscular atrophy” (SMA) in a mouse by designing and making a transgenic mouse model capable of expressing the transgene of Flag-mZPR1 (see, e.g., Kannan at title, abs, 70 at col II at § “Materials and methods” to 71 at col I at §§ “Generation of SMA mice with ZPR1 overexpression (Z-SMA)”, Supp. Fig. 1A-E ).
Regarding instant claim 1-2, 8-10, 20, 23, and the administration and/or expression of a zinc finger protein ZPR1 or nucleotide encoding ZPR1, Kannan discloses a model wherein a transgene encoding mouse ZPR1 is delivered to mice via “injection of linearized vector DNA into male pronucleus” (see, e.g., Kannan at title, abs, 70 at col II at § “Materials and methods” to 71 at col I at §§ “Generation of SMA mice with ZPR1 overexpression (Z-SMA)”, Supp. Fig. 1A; see esp. id. at 70 at col II at final ¶). Accordingly, the mice are understood to encode a ZPR1 transgene (DNA), that expresses ZPR1 encoding mRNA, which expresses ZPR1 protein, which results in treatment of SMA (see id).
Regarding instant claims 1, 3, 11-12, and a ZPR1 protein having “at least 65% sequence homology” to instant SEQ ID NO: 2 or a nucleotide encoding a sequence sharing “at least 65% sequence homology to SEQ ID NO: 1”, the phrase “65% sequence homology” has been rejected as indefinite and lacking written description (see, e.g., rejections under 35 USC §112(a) and §112(b), above; those discussions are incorporated herein). For purposes of the instant rejection, mouse ZPR1 is understood to be homologous with human ZPR1. This is pertinent because Kannan refers to the encoded transgene as “Mouse Zpr1” (see, e.g., Kannan at Supp. Fig. 1A). Critically, NP_035882.1 is understood to be the protein encoded by “Mouse Zpr1” (see, e.g., NP_035882.1 at 1 at “Reference 1”, noting that “Reference 1” is Kannan); this is pertinent because the protein encoded by “Mouse Zpr1” (see, e.g., Kannan at Supp. Fig. 1A; see also NP_035882.1 at 1 at “Reference 1” and at 3 at sequence) shares >90% sequence identity with instant SEQ ID NO: 2 (compare instant SEQ ID NO:2 with NP_035882.1 mouse ZPR1, showing 415/459 identities or 90.4% sequence identity). Furthermore, NM_011752.2 is understood to be the mRNA encoded by “Mouse Zpr1” (see, e.g., NP_035882.1 at 1 at “Reference 1”, noting that “Reference 1” is Kannan); this is pertinent because the mRNA encoded by “Mouse Zpr1” (see, e.g., Kannan at Supp. Fig. 1A; see also NP_035882.1 at 1 at “Reference 1” and at 3 at sequence) shares 1205/1381 identities or >87% sequence identity with instant SEQ ID NO: 1 (compare instant SEQ ID NO:1 with NM_011752.2 mouse ZPR1 mRNA, showing 1205/1381 identities or >87% sequence identity). Accordingly, the mice treated as described by Kannan (see, e.g., Kannan at title, abs, 70 at col II at § “Materials and methods” to 71 at col I at §§ “Generation of SMA mice with ZPR1 overexpression (Z-SMA)”, Supp. Fig. 1A; see esp. id. at 70 at col II at final ¶) are understood to necessarily and inherently express, via transgenic administration, a ZPR1 transgene (DNA), that expresses ZPR1 encoding mRNA, which expresses ZPR1 protein, which results in treatment of SMA (see id), wherein such sequences are homologous to instant SEQ ID NOs: 1 and 2.
Regarding transgenic administration, the transgenic mouse model capable of expressing the transgene of Flag-mZPR1 and treating SMA was made by “injection of linearized vector DNA into male pronucleus” (see, e.g., Kannan at title, abs, 70 at col II at § “Materials and methods” to 71 at col I at §§ “Generation of SMA mice with ZPR1 overexpression (Z-SMA)”, Supp. Fig. 1A; see esp. id. at 70 at col II at final ¶).
Regarding instant claims 20, 23, and “wherein the administered or expressed ZPR1 treats or prevents SMA by decreasing R-loop accumulation”, per MPEP § 2111.04(I), “Claim scope is not limited by claim language that . . . . does not require steps to be performed, or by claim language that does not limit a claim to a particular structure”, and further states that a “whereby clause” in a claim “is not given weight when it simply expresses the intended result of a process step positively recited”. Here, the transgenic administration or expression of the transgene of Flag-mZPR1 in SMA mice would be understood to necessarily and inherently function the same regardless of an artisan’s intent (see, e.g., In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990), noting that a chemical composition and its properties are inseparable because "Products of identical chemical composition can not have mutually exclusive properties."). In addition to the inherency argument above, it is noted that Kannan explicitly teaches and discloses that administered or expressed ZPR1 decreases R-loop accumulation (see, e.g., Kannan at title, abs, 70 at col II at 1st full ¶, 81 at col II at 1st ¶, 83 at col I at 1st partial ¶, 83 at col II at 1st partial ¶, Fig. 5 at 82-83, Fig. 6 at 85-86, Fig. 8 at 89). Accordingly, it was well-known in the prior art that ZPR1 transgenic expression treated SMA by decreasing R-loop accumulation.
Regarding instant claims 1, 25, and a subject that is a mammal, Kannan explicitly reduces to practice a method of treating “spinal muscular atrophy” (SMA) in a transgenic mouse model (see, e.g., Kannan at title, abs, 70 at col II at § “Materials and methods” to 71 at col I at §§ “Generation of SMA mice with ZPR1 overexpression (Z-SMA)”, Supp. Fig. 1A-E ).
Accordingly, claims 1-3, 8-12, 17, 20, 23, and 25 are rejected as anticipated by the prior art.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 1-3, 8-12, 17, 20, 23, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Kannan et al27 as evidenced by NP_035882.128 and NM_011752.229 as applied to claims 1-3, 8-12, 17, 20, 23, and 25 above, and further in view of NP_003895.130 and NM_003904.531.
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and those interpretations are incorporated into the instant rejection. “SMA” is understood to be “spinal muscular atrophy”. The instant rejection addresses the usage of two different human sequences and the usage of gene therapy administration routes. Additional claim interpretations are set forth below.
The teachings of Kannan as evidenced by NP_035882.1 and NM_011752.2 have been discussed above in a preceding rejection, and those teachings are incorporated herein.
The teachings of Kannan as evidenced by NP_035882.1 and NM_011752.2 differ from a non-elected species as follows: Kannan does not explicitly reduce to practice a method of treating a human subject for SMA by administering human ZPR1 protein and/or nucleotides encoding ZPR1 protein.
However, Kannan is understood to provide an animal model proof-of-principle for the treatment of SMA (see, e.g., Kannan at title, abs, 70 at col II at § “Materials and methods” to 71 at col I at §§ “Generation of SMA mice with ZPR1 overexpression (Z-SMA)”, 73 at col I-II at § “Results”, Fig. 1 on 74-75, Fig. 2 on 76-77, Fig. 3 on 78, Fig. 4 on 80-81, Fig. 5 on 82-83, 88 at col I-II at § “Discussion”, 89 at Fig. 8 showing a graphical representation of the mechanism of ZPR1-dependent rescue of spinal muscular atrophy, 91-92 at bridging ¶, 92 at col I at 1st full ¶, Supp. Fig. 1A-E). Furthermore, Kannan provides explicit guidance and direction directing artisans to treat SMA in humans by administering human ZPR1 sequences to patients having SMA:
Moreover, the development of an actual therapeutic strategy for the treatment of SMA may utilize . . . . a gene therapy method using AAV9 vector to deliver AAV9-ZPR1 intravenously.
(see, e.g., Kannan at 92 at col I at 1st partial ¶).
Accordingly, an artisan would readily appreciate and envisage a method of treating SMA in humans involving the intravenously administering AAV9 vectors encoding human ZPR1 in view of the explicit guidance of Kannan.
Regarding instant SEQ ID NOs: 1-2, in view of the guidance of Kannan directing artisans to treat SMA in humans by administering human ZPR1 sequences to patients having SMA:
Moreover, the development of an actual therapeutic strategy for the treatment of SMA may utilize . . . . a gene therapy method using AAV9 vector to deliver AAV9-ZPR1 intravenously.
(see, e.g., Kannan at 92 at col I at 1st partial ¶).
An artisan would reasonably review the prior art for suitable human ZPR1 sequences. An artisan would begin by simply reviewing the sequences associated with the Kannan document in NCBI databases, which would direct artisans to the protein sequence of NP_003895.1 and the mRNA sequence of NM_003904.5. Both sequences share 100% sequence identity with instant SEQ ID NO: 2 and 1, respectively, and both sequences are associated with the Kannan reference (see, e.g., NP_003895.1 at Reference 1 on page 1, noting that Reference 1 is Kannan; see also NM_003904.5 at Reference 1 on page 1, noting that Reference 1 is Kannan). Accordingly, human sequences for ZPR1 suitable for use in clinical therapeutic strategies were already known and disclosed as associated with the primary reference in the prior art.
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 simply combination of prior art elements (i.e., the known vector of AAV9, the known sequence of NM_003904.5) according to known methods of gene therapy to predictably treat human patients with SMA by predictably expressing ZPR1 in patients exactly as suggested by the primary reference (see, e.g., MPEP § 2143(I)(A), (G)). Furthermore, each prior art element would merely perform its art-recognized function in combination as taught separately. In addition, or alternatively, the invention is the application of the known technique of treating SMA by administering or expressing ZPR1 in a subject to human gene therapy techniques, wherein gene therapy methods could predictably utilize an AAV9 vector to deliver AAV9-ZPR1 intravenously to humans with SMA to predictably treat SMA, exactly as taught and suggested by the primary reference (see, e.g., MPEP § 2143(I)(C), (D), (F), and (G)).
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.
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, it is well-within the ordinary skill in the art to administer a known compound in a known manner to a known patient population to treat a known disease, wherein the mechanism of action was already known and documented in the prior art.
Accordingly, claims 1-3, 8-12, 17, 20, 23, and 25 are rejected as obvious.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RANDALL L BEANE whose telephone number is (571)270-3457. The examiner can normally be reached Mon.-Fri., 7 AM to 2 PM ET.
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/RANDALL L BEANE/Primary Examiner, Art Unit 1654
1 NP_003895.1, zinc finger protein ZPR1 isoform 1 [Homo sapiens], NCBI Protein Database, 3 pages (PRI 07-SEP-2020); also available at https://www.ncbi.nlm.nih.gov/protein/4508021?sat=48&satkey=134168120 (last visited 6/12/2026).
2 NP_035882.1, zinc finger protein ZPR1 [Mus musculus]. NCBI Protein Database, 3 pages, (ROD 26-AUG-2020); also available at https://www.ncbi.nlm.nih.gov/protein/6756053?sat=48&satkey=133730324 (last visited 6/12/2026).
3 NM_003904.5, Homo sapiens ZPR1 zinc finger (ZPR1), transcript variant 1, mRNA, NCBI GenBank Database, 6 pages, (PRI 07-SEP-2020); also available at https://www.ncbi.nlm.nih.gov/nuccore/1519243649?sat=48&satkey=134168120 (last visited 6/12/2026)
4 see, e.g., Nystrom v. TREX Co., Inc., 424 F. 3d 1136, 1143 (Fed. Cir. 2005), explaining that "When different words or phrases are used in separate claims, a difference in meaning is presumed.
5 See previous footnote.
6 See previous footnote.
7 Kannan et al., ZPR1 prevents R-loop accumulation, upregulates SMN2 expression and rescues spinal muscular atrophy. Brain. 2020 Jan 1; 143(1):69-93, 1-10 of Supp, published online Dec. 12, 2019; doi: 10.1093/brainawz373; hereafter “Kannan”; cited in Requirement mailed 1/12/2026.
8 The originally filed disclosure appears to conflate SEQ ID NO: 1 (nucleotide sequence) with SEQ ID NO: 2 (peptide sequence) throughout. However, this is a clear typographical error and the correction is obviously the only other sequence identified on record (i.e., only two sequences are disclosed).
9 NP_035882.1, zinc finger protein ZPR1 [Mus musculus]. NCBI Protein Database, 3 pages, (ROD 26-AUG-2020); also available at https://www.ncbi.nlm.nih.gov/protein/6756053?sat=48&satkey=133730324 (last visited 6/12/2026).
10 NP_003895.1, zinc finger protein ZPR1 isoform 1 [Homo sapiens], NCBI Protein Database, 3 pages (PRI 07-SEP-2020); also available at https://www.ncbi.nlm.nih.gov/protein/4508021?sat=48&satkey=134168120 (last visited 6/12/2026); hereafter “HumanZPR1”.
11 Human ZPR1 is located on Chromosome 11.
12 The originally filed disclosure appears to conflate SEQ ID NO: 1 (nucleotide sequence) with SEQ ID NO: 2 (peptide sequence) throughout. However, this is a clear typographical error and the correction is obviously the only other sequence identified on record (i.e., only two sequences are disclosed).
13 Koonin et al., Chapter 2 Evolutionary Concept in Genetics and Genomics, Sequence - Evolution - Function: Computational Approaches in Comparative Genomics. Boston: Kluwer Academic; 2003; NCBI Bookshelf; attached as pdf, 25 pages; hereafter “Koonin”.
14 Webber et al., Genes and homology, Current Biology, vol. 14(9):R:332-R333 (May 4, 2004); hereafter “Webber”.
15 Rost, Twilight zone of protein sequence alignments, Protein Engineering, vol. 12(2):85-94 (1999)).
16 The originally filed disclosure appears to conflate SEQ ID NO: 1 (nucleotide sequence) with SEQ ID NO: 2 (peptide sequence) throughout. However, this is a clear typographical error and the correction is obviously the only other sequence identified on record (i.e., only two sequences are disclosed).
17 The originally filed disclosure appears to conflate SEQ ID NO: 1 (nucleotide sequence) with SEQ ID NO: 2 (peptide sequence) throughout. However, this is a clear typographical error and the correction is obviously the only other sequence identified on record (i.e., only two sequences are disclosed).
18 Human ZPR1 is located on Chromosome 11.
19 See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984)
20 The originally filed disclosure appears to conflate SEQ ID NO: 1 (nucleotide sequence) with SEQ ID NO: 2 (peptide sequence) throughout. However, this is a clear typographical error and the correction is obviously the only other sequence identified on record (i.e., only two sequences are disclosed).
21 Koonin et al., Chapter 2 Evolutionary Concept in Genetics and Genomics, Sequence - Evolution - Function: Computational Approaches in Comparative Genomics. Boston: Kluwer Academic; 2003; NCBI Bookshelf; attached as pdf, 25 pages; hereafter “Koonin”.
22 Webber et al., Genes and homology, Current Biology, vol. 14(9):R:332-R333 (May 4, 2004); hereafter “Webber”.
23 Rost, Twilight zone of protein sequence alignments, Protein Engineering, vol. 12(2):85-94 (1999)).
24 Kannan et al., ZPR1 prevents R-loop accumulation, upregulates SMN2 expression and rescues spinal muscular atrophy. Brain. 2020 Jan 1; 143(1):69-93, 1-10 of Supp, published online Dec. 12, 2019; doi: 10.1093/brainawz373; hereafter “Kannan”; cited in Requirement mailed 1/12/2026.
25 NP_035882.1, zinc finger protein ZPR1 [Mus musculus]. NCBI Protein Database, 3 pages, (ROD 26-AUG-2020); also available at https://www.ncbi.nlm.nih.gov/protein/6756053?sat=48&satkey=133730324 (last visited 6/12/2026).
26 NM_011752.2, Mus musculus ZPR1 zinc finger (Zpr1), mRNA, NCBI GenBank database, 4 pages, (ROD-26-AUG-2020); also available at https://www.ncbi.nlm.nih.gov/nuccore/133778942?sat=48&satkey=133730324 (last visited 6/12/2026).
27 Kannan et al., ZPR1 prevents R-loop accumulation, upregulates SMN2 expression and rescues spinal muscular atrophy. Brain. 2020 Jan 1; 143(1):69-93, 1-10 of Supp, published online Dec. 12, 2019; doi: 10.1093/brainawz373; hereafter “Kannan”; cited in Requirement mailed 1/12/2026.
28 NP_035882.1, zinc finger protein ZPR1 [Mus musculus]. NCBI Protein Database, 3 pages, (ROD 26-AUG-2020); also available at https://www.ncbi.nlm.nih.gov/protein/6756053?sat=48&satkey=133730324 (last visited 6/12/2026).
29 NM_011752.2, Mus musculus ZPR1 zinc finger (Zpr1), mRNA, NCBI GenBank database, 4 pages, (ROD-26-AUG-2020); also available at https://www.ncbi.nlm.nih.gov/nuccore/133778942?sat=48&satkey=133730324 (last visited 6/12/2026).
30 NP_003895.1, zinc finger protein ZPR1 isoform 1 [Homo sapiens], NCBI Protein Database, 3 pages (PRI 07-SEP-2020); also available at https://www.ncbi.nlm.nih.gov/protein/4508021?sat=48&satkey=134168120 (last visited 6/12/2026).
31 NM_003904.5, Homo sapiens ZPR1 zinc finger (ZPR1), transcript variant 1, mRNA, NCBI GenBank Database, 6 pages, (PRI 07-SEP-2020); also available at https://www.ncbi.nlm.nih.gov/nuccore/1519243649?sat=48&satkey=134168120 (last visited 6/12/2026)
Prosecution Insights