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 and 6-13 are pending. Claims 12-13 are withdrawn as directed to a non-elected invention.
Election/Restriction
Applicant’s election of Group I (i.e., claims 1-4 and 6-11 as filed 3/13/2023) and the species of in vivo treatment of rats having a supraspinatus tendon defect with ZKscan8-introduced umbilical cord-derived mesenchymal stem cells in the reply filed on 4/06/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
The originally elected species is understood as follows: The originally elected species is understood to be the method of in vivo treatment of rats having a surgically-introduced supraspinatus tendon defect with ZKscan8-introduced umbilical cord-derived mesenchymal stem cells at a dosage of 1x106 cells/10µL via local injection to the ruptured tendon, as disclosed at pages 29-31 of the Specification filed 1/25/2023 (see, e.g., Reply filed 4/06/2026 at 2, note that the identified pages are incorrect as § “Design of animal experiment” begins at page 29). The “ZKscan8-introduced umbilical cord-derived mesenchymal stem cells” are understood to be human umbilical cord-derived stem cells modified using a pscAAV vector plasmid (i.e., adenovirus). The model system of surgically-introduced supraspinatus tendon defect is understood to model tendinitis (see, e.g., Spec. at 8 at lines 8-10, referring to the examples as “a tendinitis-induced rat”). The originally elected species is understood to read upon instant claims 1-4 and 6-11.
Following extensive search and examination, the originally elected species of treating a surgically-introduced supraspinatus tendon defect by administering 1x106 cells/10µL via local injection to the subject, wherein the cells are “ZKscan8-introduced” umbilical cord-derived mesenchymal stem cells (wherein “ZKscan8-introduced” is understood to mean that the cells comprise a pscAAV vector plasmid encoding the protein of instant SEQ ID NO: 2), has been deemed free of the prior art. The point of novelty is the combination of all limitations, including the explicit presence of a pscAAV vector encoding SEQ ID NO: 2 in a surgically-introduced supraspinatus tendon defect model.
Following extensive search and examination, the originally elected species has been deemed free of the prior art. Per MPEP § 803.02(III)
If the examiner determines that the elected species is allowable over the prior art, the examination of the Markush claim will be extended. If prior art is then found that anticipates or renders obvious the Markush claim with respect to a nonelected species, the Markush claim shall be rejected; claims to the nonelected species would still be held withdrawn from further consideration. The prior art search will not be extended unnecessarily to cover all nonelected species.
Accordingly, Examination was extended to a non-elected species of a cell culture product (i.e., extracellular vesicles) of UC-MSCs comprising linear DNA comprising instant SEQ ID NO: 2, wherein the cell culture product is administered to a surgically-introduced tendon defect model. Following extensive search and examination, this non-elected species has been rejected as anticipated in view of the prior art. Per MPEP § 803.02(III), claims directed to other nonelected species have been withdrawn.
Claims 12-13 are 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. Election was made without traverse in the reply filed on 4/06/2026.
Claims 1-4 and 6-11 are presently considered.
Priority
The priority claim to PCT/KR2021/008402 (filed 7/02/2021) is acknowledged.
Examiner notes that no certified translation of the Foreign Application KR10-2020-0095892 (filed 7/31/2020) has been placed on record. If applicant wants the application to be accorded benefit of the non-English language application, a certified translation is required (see 35 U.S.C. 119(b)(3), 37 CFR 1.55(g)(1)-(4)). Applicant is advised that any showing of priority that relies on a non-English language application is prima facie insufficient if no certified translation of the application is on file. See 37 CFR 41.154(b).
Information Disclosure Statement
The IDS filed 1/25/2023 and 12/30/2024 are acknowledged and presently considered.
Applicant should note that one or more documents disclosed on the IDS form submitted on 12/30/2024 were not considered since they did not conform to 37 CFR 1.98(b) by providing a proper date, as 37 CFR 1.98(b) requires that each publication must be identified by publisher, author (if any), title, relevant pages of the publication, and date and place of publication. The date of publication supplied must include at least the month and year of publication, except that the year of publication (without the month) will be accepted if the applicant points out in the information disclosure statement that the year of publication is sufficiently earlier than the effective U.S. filing date and any foreign priority date so that the particular month of publication is not in issue. See MPEP 609.04(a). Here, the earliest priority claim is to KR10-2020-0095892 (filed 7/31/2020); therefore, all documents published in 2019 or later must be accompanied by both month and date of publication.
References that were not considered have been indicated by strike-though on the attached IDS forms. Although not considered, these documents have been placed in the application file, but the information referred to therein has not been considered as to the merits. Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
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 as filed 3/13/2023 is representative of the pending claim scope and presently recites:
1. A method for treating an inflammatory disease in a subject in need thereof, comprising administering to the subject a Zkscan8 (zinc finger protein with KRAB and SCAN domains 8) protein, a Zkscan8 gene, a vector comprising the Zkscan8 gene, a cell comprising the vector, or a culture of the cell as an active ingredient.
Accordingly, the claims are directed to a method of treating inflammatory diseases in subjects, in vivo, by administering to the subject a composition or compound. Applicable claim interpretations are discussed below.
A “Zkscan8 … protein” and a “ZKscan8 gene” are recited at claim 1, but are identified as encompassing a vast and highly varied genus of ill-defined sequences. Specifically, the term “ZKscan8 protein” is defined functionally by stating that the term includes any “variant” or “functional equivalent thereof”, including “a polypeptide which has a sequence homology of 60%.... or higher”, or otherwise a sequence resulting from “the addition, substitution, or deletion of amino acids” that “exhibits substantially the same activity as the ZKscan8 protein of the present disclosure” (see, e.g., Spec. filed 1/25/2023 at 4-5 at bridging ¶). For purposes of applying prior art, the term is understood to include at least polynucleotides encoding instant SEQ ID NO: 1, and peptides comprising instant SEQ ID NO: 2.
Instant SEQ ID NO: 2 is identified as a “Zkscan8” protein at claim 2. Upon BLAST search, SEQ ID NO: 2 is understood to be a naturally-occurring human protein (see, e.g., NP_001265048 at § Definition on 1, and § References at 1-2) also known as NP_001265048.11, LD5-1; ZNF192; and ZSCAN40; wherein the gene name is “ZKSCAN8” (see, e.g., NP_001265048 at page 3 at § CDS).
“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)).
“Administering” is defined in the specification to “refer[] to administration of a therapeutically effective amount of the composition of the present disclosure directly into a subject” (see, e.g., Spec. filed 1/25/2023 at 7), wherein “therapeutically effective amount” is defined as including a “prophylactically effective amount” (see, e.g., Spec. filed 1/25/2023 at 7). Accordingly, the claim scope, by definition, is directed to administering a “therapeutically effective” amount to patients. For purposes of applying prior art, the amount is deemed a “therapeutically effective amount” if a therapeutic is obtained or expected.
“For treating” is interpreted as an intended use, as described in the Specification (see, e.g., Spec. filed 1/25/2023 at 7), including inhibition, alleviation, or removal of a disease, disorder or symptom (see id).
“Subject in need thereof” is understood to include any subject (see, e.g., Spec. filed 1/25/2023 at 7-8 at bridging ¶, defining subject as any human, mouse, rat, horse, cat, dog, guinea pig, cow, pig, monkey, chimpanzee, baboon or rhesus monkey) that is “in need thereof” for treatment (including prophylactic treatment) of any type of inflammatory disease. Because prophylactic treatment is encompassed by the claims, the claims are understood to encompass all patients at risk of developing any type of inflammatory disease.
A “culture of the cell as an active ingredient” is undefined on record, and it is unclear if the term refers to dedifferentiated cells, cell suspensions, secondary metabolites, cell lysates/extracts, secreted components, etc. The claim already claims and recites proteins, polynucleotides encoding proteins, and cells comprising polynucleotides encoding proteins, and therefore it is prima facie unclear what different or nuanced structure(s) pertaining to ZKscan8 are supposed to be captured by this language. For purposes of examination, a “culture” is presumed to not require any ZKscan8 protein or gene to be present “as an active ingredient”, but wherein such language broadly encompasses any culture product, including extracellular vesicles.
A “vector” is not defined, but is exemplified as including any linear DNA, plasmid DNA, recombinant viral vector (see, e.g., Spec. filed 1/25/2023 at 9 at lines 19-23). A “vector” may be included in a cell (see, e.g., Spec. filed 1/25/2023 at 10 at lines 6-10). The only “vector” reduced to practice is understood to be a pscAAV vector (see, e.g., Spec. filed 1/25/2023 at 10-11 at bridging ¶). The term “vector” is interpreted consistent with its usage in the art and is understood to mean any “nucleic acid or nucleic acid-bearing particle, cell, or organism capable of being used to transfer a nucleic acid into a host cell” (see, e.g., US 10612011 B2 at col. 36 at lines 35-60).
Regarding the clause stating “wherein the composition inhibits the expression or activity of…. and increases the expression of …” at claim 11: 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 “wherein” clause does not unambiguously correspond to a clear structure/function relationship in the original disclosure, and therefore is not a functional limitation. Rather, the “wherein” clause is understood to merely recite an intended or expected result fully satisfied by the positively recited steps and/or structures set forth in the body of the claim. Therefore, the “wherein” clause of claim 11 is understood to be fully satisfied by all prior art embodiments that satisfy the structural requirements and active method steps recited in the body of claim 1.
Additional claim interpretations are discussed below.
Objections to the Specification
The disclosure is objected to because of the following informalities:
Sequence Listing: The instant disclosure is objected to for not complying with 37 C.F.R. 1.821 as detailed in MPEP §§ 2421–2424. Specifically, the instant application does not comply with 37 C.F.R. 1.821(b)-(e). The instant claims and/or disclosure contain references or disclosures of amino acid sequences that should be accompanied by a sequence listing and identified using "SEQ ID NOs” as prescribed (see, MPEP §§ 2421–2424). Specifically, the instant application discloses sequences at page 22 at lines 15-20, which are not accompanied by a SEQ ID NO.
Embedded Hyperlinks: The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see, e.g., Spec. filed 1/25/2023 at 20 at lines 1-5, p. 20 at lines 14-16). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Trade Names, Trademarks and Other marks Used in Commerce: The use of the term CYTOSCAPE2 (see, e.g., Spec. filed 1/25/2023 at 20), RNEASY3 (see, e.g., Spec. filed 1/25/2023 at 20 at line 24), TRUSEQ4 (see, e.g., Spec. filed 1/25/2023 at 21 at line 2); etc. (this is not an exhaustive listing) which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Appropriate correction is required.
Drawings
The drawings are objected to because the images are not fully legible (see, e.g., Figures 1(a), 1(b)) or do not show the claimed structures (see, e.g., Figures 11(b)-(e), noting that “Normal” is listed in the index, but no corresponding rectangle is actually shown or visible corresponding to this control). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 1-2 are objected to because of the following informalities:
Claim 1 recites “the Zkscan8 gene”, “the vector”, and “the cell”; however, “Zkscan8 … protein” and a “ZKscan8 gene” as recited at claim 1 are generic compounds (see claim interpretation section above; see also Spec. filed 1/25/2023 at 4-5 at bridging ¶). Accordingly, claim 1 should presumably recite
1. A method for treating an inflammatory disease in a subject in need thereof, comprising administering to the subject a Zkscan8 (zinc finger protein with KRAB and SCAN domains 8) protein, a Zkscan8 gene, a vector comprising a Zkscan8 gene, a cell comprising a vector comprising a Zkscan8 gene, or a culture of a cell comprising a vector comprising a Zkscan8 gene as an active ingredient.
Claim 2 is objected to because it contains redundant and superfluous language that fails to meaningfully limit the pending claim scope. Specifically, claim 2 recites “wherein the Zkscan8 is represented by an amino acid sequence of SEQ ID NO: 2”, which is understood to mean “wherein ZKscan8 is SEQ ID NO: 2”. Redundant and superfluous language should be removed to enhance claim clarity and to minimize potential confusion. Examiner suggests the following amendments:
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 1-4, and 6-11 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 recites and refers to “a ZKscan8” protein and gene, but “ZKscan8” is ambiguously defined on record in a manner inconsistent with its usage in the art (see, e.g., Spec. filed 1/25/2023 at 4-5 at bridging ¶, noting that the term is broadly defined using references to percent homology, and by reference to structures that exhibit a function, namely “exhibits substantially the same activity as the ZKscan8 protein of the present disclosure”, that fails to meaningfully correspond to any structure/function relationship of record having clear metes and bounds). Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). Here, although it is clear that the terms encompass the polynucleotide of instant SEQ ID NO: 1 and the polypeptide of SEQ ID NO: 2, it is unknown what other structures are included or excluded by the pending claim scope because
References to “percent homology” lack any clear definition or meaning in the art because “homology”, “sequence similarity”, and “sequence identity” are distinct concepts as explained by the prior art of Rost5. Rost identifies that proteins can be 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), and 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). Therefore, attempts to define a genus by reference to a percent homology render the metes and bounds of the genus indefinite.
Similarly, references to structures of unknown metes and bounds by simply reciting a functional limitation that such structures are intended to achieve does not meaningfully permit an artisan to avoid infringement in the absence of a structure/function relationship commensurate in scope with the functional limitation (see, e.g., Spec. filed 1/25/2023 at 4-5 at bridging ¶, defining structures by reference to a functional limitation, namely structures that “exhibit[] substantially the same activity as the ZKscan8 protein of the present disclosure”, which is not further explained or correlated to structures).
Therefore, the genus of structures encompassed by reference to “a ZKscan8” protein or gene is indefinite because the specification does not clearly redefine the term commensurate in scope with the description set forth in the instant disclosure (see, e.g., Spec. filed 1/25/2023 at 4-5 at bridging ¶). 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 constitute “a ZKscan8” protein or gene at claim 1, the pending claim scope is indefinite. For purposes of applying prior art, the term is understood to include at least polynucleotides encoding instant SEQ ID NO: 1, and peptides comprising instant SEQ ID NO: 2.
Claim 1 recites a “culture of the cell as an active ingredient”, which is undefined on record. It is prima facie unknown if the term includes or excludes dedifferentiated cells, cell suspensions, secondary metabolites, cell lysates/extracts, secreted components, etc., or if the term requires “a ZKscan8” protein or gene to be present or not. Notably, the claim already claims and recites proteins, polynucleotides encoding proteins, and cells comprising polynucleotides encoding proteins, and therefore it is unclear what different or nuanced structure(s) pertaining to ZKscan8 are captured by this language. However, close prior art exists wherein cultures of Mesenchymal Stromal cells derived from umbilical cords are utilized to derive a culture product, namely extracellular vesicles, which is administered to subjects and used to treat tendon defects, including tendonitis, tendinitis, tendinosis, paratendinitis, tenocynovitis, peritendinitis, etc. (see, e.g., WO2018/130554A1 at 29 at final ¶, 30 at 1st ¶, 44-45 at bridging ¶, 45 at 1st full ¶, claims 1-2 and 32). It is unclear if this art anticipates the claimed invention or not, because it is unclear what the metes and bounds of a “culture of the cell as an active ingredient” does nor does not include. For purposes of applying prior art, a “culture of the cell as an active ingredient” is reasonably inferred to read upon any compound or composition isolatable from a cell culture, including extracellular vesicles and components lacking “a ZKscan8” protein or gene.
Claim 1 recites “administering to the subject”, wherein “administering” is functionally defined in the specification, and “refers to administration of a therapeutically effective amount of the composition of the present disclosure directly into a subject” (see, e.g., Spec. filed 1/25/2023 at 7, emphasis added). Accordingly, the step of administering at claim 1 is only performed as claimed when a “therapeutically effective amount of the composition” is given “directly into a subject”; which raises a substantial and material concern, namely “what constitutes a therapeutically effective amount?” Regarding the usage of functional limitations, 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 claims. Here, the instant disclosure provides a functional definition of “therapeutically effective amount”, which is circular in nature (see, e.g., Spec. filed 1/25/2023 at 7, noting that it means “an amount enough to provide a therapeutic or prophylactic effect in a subject”), but identifies multiple factors that functionally impact sufficient dosages without explaining how to determine a dosage of the claimed compositions that constitute a “therapeutically effective amount” (see, e.g., Spec. filed 1/25/2023 at 12 at 2nd full ¶). At best, the specification generically identifies that a “preferred administration dosage” in an unspecified formulation of an unspecified composition “for an adult” is within a range covering five orders of magnitude (see id., disclosing “0.001 to 100 mg/kg”) but without specifying if this range for an adult is pertinent to a protein, nucleic acid, cell culture product, etc. as claimed, or pertinent for oral administration, topical administration, subdermal administration, intraocular administration, etc., etc. This is pertinent because close prior art exists (see, e.g., Coyle et al.6 at title, abs, noting that placentophagy, wherein a placenta is eaten raw, has been documented in humans; note that SEQ ID NO: 2 is a naturally occurring peptide and therefore the gene is naturally present in human placental cells), but it is unclear if such prior art satisfies the functionally defined “administering” step at claim 1 by delivering a “therapeutically effective amount” or a “ZKscan8 gene” as required by the claim. 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 methods, claim 1 is rejected as indefinite.
Claims 2-4 and 6-11 depend directly or indirectly from an indefinite claim, and fail to reconcile the indefiniteness of that claim. Accordingly, claims 2-4 and 6-11 are indefinite because they depend from an indefinite base claim.
Claims 1-4 and 6-11 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 1-4 and 6-11 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 claim scope is ill-defined and it is unclear what does or does not constitute (i) a “culture of the cell as an active ingredient” as recited in the claims; (ii) “a ZKscan8” protein and gene commensurate in scope with the claims; or (iii) “administering” (i.e., the term is functionally defined to require a “therapeutically effective amount”) commensurate in scope with the claims. Accordingly, it is unknown what compounds and treatments do or do not read upon the instant claims scope.
Claim Scope
Claim 1 is representative of the pending claims scope and applicable claim interpretations have been discussed above under 35 USC § 112(b) and in a separate section (i.e., “Claim Interpretation” section) above, and those discussions are incorporated herein.
Claim 1 recites a “culture of the cell as an active ingredient”, which is undefined on record. It is prima facie unknown if the term includes or excludes dedifferentiated cells, cell suspensions, secondary metabolites, cell lysates/extracts, secreted components, etc., or even if the resulting “culture” requires the presence of “a ZKscan8” protein or gene or not. Accordingly, the description is inadequate to reasonably inform artisans of what does or does not constitute the invention as presently claimed.
As explained under 35 USC § 112(b) and in the claim interpretation section above, the term “a ZKscan8” protein and gene is functionally defined on record (see, e.g., Spec. filed 1/25/2023 at 4-5 at bridging ¶, noting that the term is broadly defined to include all structures that exhibit a function, namely “exhibits substantially the same activity as the ZKscan8 protein of the present disclosure”). This functional definition is problematic because it fails to actually correspond to any structure/function relationship known in the art or otherwise disclosed on record, which would reasonably permit an artisan to identify de novo what exact structures do or do not constitute “a ZKscan8” that “exhibits substantially the same activity as the ZKscan8 protein of the present disclosure” (i.e., presumably instant SEQ ID NO: 2) (see, e.g., Spec. filed 1/25/2023 at 4-5 at bridging ¶). For example, derivatives sharing 95% sequence identity with instant SEQ ID NO: 2 or having a mutation at position 108 may be included or excluded from the claim scope--it is unknown because no clarification is provided regarding portions of SEQ ID NO: 2 that may be altered while retaining functionality. Rather, the term appears to simply describe what Applicant hopes and wishes to achieve, without actually identifying what structure is sufficient to achieve that outcome. Accordingly, the metes and bounds of what constitutes infringement of the claimed invention is left for future artisans to experimentally determine and discover.
As explained under 35 USC § 112(b) and in the claim interpretation section above, the term “a ZKscan8” protein and gene is ill-defined on record (see, e.g., Spec. filed 1/25/2023 at 4-5 at bridging ¶, noting that the term is broadly defined using references to percent homology). References to a percent homology are meaningless in view of the art, because homology either exists or does not exist, and “homology”, “sequence similarity”, and “sequence identity” are distinct concepts as explained by the prior art of Rost7. For example, Rost identifies that proteins can be 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), and 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). Therefore, attempts to define a genus by reference to a percent homology render the metes and bounds of the genus indefinite. Accordingly, such scientifically inaccurate descriptions fail to reasonably inform artisans of the metes and bounds of what does or does not constitute infringement of the claimed invention.
Claim 1 recites “administering to the subject”, wherein “administering” is functionally defined in the specification, and “refers to administration of a therapeutically effective amount of the composition of the present disclosure directly into a subject” (see, e.g., Spec. filed 1/25/2023 at 7, emphasis added). This functional definition is pertinent because presumably prior art does not read upon the claims unless the administered compound is present in a “therapeutically effective amount of the composition” that is given “directly into a subject”. However, this raises a substantial and material concern, namely “what constitutes a therapeutically effective amount of a protein, gene, cell, or ‘culture’ sufficient to treat a particular patient for a particular disease or disorder within the scope of claims 3 and 4?”. However, the instant disclosure provides only a functional definition of “therapeutically effective amount”, which is circular in nature and provides minimal guidance (see, e.g., Spec. filed 1/25/2023 at 7, noting that it means “an amount enough to provide a therapeutic or prophylactic effect in a subject”). The guidance is minimal because the Specification also identifies multiple factors that functionally impact sufficient dosages without explaining how to determine a dosage of the claimed compositions that constitute a “therapeutically effective amount” for a particular structure, administration route, and patient population (see, e.g., Spec. filed 1/25/2023 at 12 at 2nd full ¶). Although the specification generically identifies that a “preferred administration dosage” in an unspecified formulation of an unspecified composition “for an adult” is within a range covering five orders of magnitude (see id., disclosing “0.001 to 100 mg/kg”), this disclosure is made without reference or clarification of what the unspecified composition is, which is relevant since the claims encompass proteins, nucleic acids, vectors, whole cells, and unspecified cell culture products; it is also unclear if the disclosed range is pertinent to oral administration, topical administration, subdermal administration, intraocular administration, sublingual administration, vaginal administration, etc., etc. Therefore, the claim scope requires and is limited to a functionally defined type of “administering” step, but fails to provide clear guidance of what does or does not constitute a “therapeutically effective amount” of any particular compound within the claim scope, for any particular route of administration, to treat any particular disease or disorder.
Accordingly, it is unclear if the claimed methods encompass trillions of species of methods of treating numerous diseases, via all forms of administration (e.g., topical, anal, oral, intramuscular, intravenous, etc.), using nucleic acids, proteins, viral particles, cells, and small molecules (“culture” products?), or if the claimed method is limited to the treatment of surgically-induced tendon defects by administering AAV-modified UM-MSC cells via local administration. Accordingly, the claim scope appears to be vast and highly varied.
Actual Reduction to Practice
One example of the claimed invention was reduced to practice, namely the originally elected species wherein rats having a surgically-introduced supraspinatus tendon defect were treated with ZKscan8-introduced umbilical cord-derived mesenchymal stem cells at a dosage of 1x106 cells/10µL via local injection to the ruptured tendon (see, e.g., Specification filed 1/25/2023 at 29-31 at § “Design of animal experiment”), wherein the “ZKscan8-introduced umbilical cord-derived mesenchymal stem cells” are understood to be human umbilical cord-derived stem cells modified using a pscAAV vector plasmid (i.e., adenovirus) comprising instant SEQ ID NO: 2 (see, e.g., id).
Zero structures constituting “a ZKscan8” protein and gene, other than instant SEQ ID NO: 1 and 2, were reduced to practice or shown to be functional in any in vivo method as claimed.
Zero examples of directly administered “ZKscan8” proteins to any patient to treat any disease was reduced to practice.
Zero examples of any directly administered nucleic acids, viruses, or genes to any patient, in the absence of a UC-MSC, were reduced to practice or shown to be functional in vivo.
Zero examples of any directly administered “culture” products of any cells were reduced to practice or shown to be functional in vivo.
Zero examples of any in vivo activity in the absence of a UC-MSC was shown on record.
Zero examples or evidence of successful treatment of “dermatitis, allergy, atopy, asthma, bronchitis, conjunctivitis, periodontitis, rhinitis, otitis media, sore throat, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn' s disease, colitis, peritonitis, osteomyelitis, meningitis, encephalitis, cystic fibrosis, stroke, hemorrhoids, gout, ankylosing spondylitis, spondyloarthropathy, enteropathy, spondylitis, rheumatic fever, lupus, fibromyalgia, psoriatic arthritis, osteoarthritis, rheumatoid arthritis” or “myositis, hepatitis, cystitis, nephritis, Sjogren's syndrome, multiple sclerosis and acute and chronic inflammatory diseases” or related animal models thereof were shown or reduced to practice.
Accordingly, one limited example was disclosed on record, and critically the only functional example of record included the administration of MSC (mesenchymal stem cells), which is relevant as explained below, because the administration of MSC alone, without Zkscan8, would be expected and predicted to treat inflammatory diseases. Accordingly, the limited in vivo methods of record do not clearly and independently establish the criticality of ZKscan8 in the absence of MSC administration.
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 of treatment using various compounds via various administration routes, at various concentrations, to treat various inflammatory disorders and diseases, but only one, highly limited species of method was reduced to practice and shown to have any functionality.
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 working species of the claimed invention does not provide sufficient disclosure to satisfy the written description requirement for the instantly claimed genus.
Furthermore, as noted above, (i) zero structures constituting “a ZKscan8” protein and gene, other than instant SEQ ID NO: 1 and 2, were reduced to practice or shown to be functional in any in vivo method as claimed; (ii) zero examples of directly administered “ZKscan8” proteins to any patient to treat any disease was reduced to practice; (iii) zero examples of any directly administered nucleic acids, viruses, or genes to any patient, in the absence of a UC-MSC, were reduced to practice or shown to be functional in vivo; (iv) zero examples of any directly administered “culture” products of any cells were reduced to practice or shown to be functional in vivo; (v) zero examples of any in vivo activity in the absence of a UC-MSC was shown on record; and (vi) zero examples or evidence of successful treatment of “dermatitis, allergy, atopy, asthma, bronchitis, conjunctivitis, periodontitis, rhinitis, otitis media, sore throat, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn' s disease, colitis, peritonitis, osteomyelitis, meningitis, encephalitis, cystic fibrosis, stroke, hemorrhoids, gout, ankylosing spondylitis, spondyloarthropathy, enteropathy, spondylitis, rheumatic fever, lupus, fibromyalgia, psoriatic arthritis, osteoarthritis, rheumatoid arthritis” or “myositis, hepatitis, cystitis, nephritis, Sjogren's syndrome, multiple sclerosis and acute and chronic inflammatory diseases” or related animal models thereof were shown or reduced to practice. 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 zero functional species 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.
The disclosure and the prior art fail to address basic threshold questions, such as “what does or does not constitute a ‘culture of the cell as an active ingredient’?” No guidance regarding whether or not such terminology includes or excludes dedifferentiated cells, cell suspensions, secondary metabolites, cell lysates/extracts, secreted components, etc., or even if the resulting “culture” requires the presence of “a ZKscan8” protein or gene or not is provided in the originally filed disclosure. This is pertinent because close prior art exists wherein cultures of Mesenchymal Stromal cells derived from umbilical cords are utilized to derive a culture product, namely extracellular vesicles, which is administered to subjects and used to treat tendon defects, including tendonitis, tendinitis, tendinosis, paratendinitis, tenocynovitis, peritendinitis, etc. (see, e.g., WO2018/130554A1 at 29 at final ¶, 30 at 1st ¶, 44-45 at bridging ¶, 45 at 1st full ¶, claims 1-2 and 32; see also rejection under 35 USC 102, below). Although for purposes of applying prior art, such disclosures are currently assumed to read upon the instant claim, it is not clear from the originally filed disclosure if such embodiments are included or excluded from the meaning of a “culture of the cell as an active ingredient”.
The disclosure and the prior art fail to address basic threshold questions, such as “what does or does not constitute a ‘a ZKscan8’ protein and gene?” No guidance is provided on record regarding how to interpret references to percent homology, or otherwise what minimal consensus sequences of SEQ ID NO: 2 are required to achieve and maintain functionality in variants of SEQ ID NO: 2 having additions, deletions, and substitutions relative to SEQ ID NO: 2 (see, e.g., Spec. filed 1/25/2023 at 4-5 at bridging ¶). Notably, the definition differs from the usage in the art, wherein the term is understood to refer to the naturally-occurring human protein of NP_001265048.18 (compare NP_001265048 with instant SEQ ID NO: 1, showing 100% identity). Zero guidance regarding functionally active variants lacking 100% sequence identity with instant SEQ ID NO: 2 have been disclosed on record.
The disclosure and the prior art fail to address basic threshold questions, such as “what amount of a protein, nucleic acid, culture product, or host cell, other than UC-MSCs, is required to treat diseases as claimed?” Although the Application provides a laundry list disclosure of things the Applicant hopes and wishes the invention to achieve, it does not clearly identify artisans of how to perform any such methods in the absence of any MSCs (i.e., UC-MSCs) (see, e.g., Specification filed 1/25/2023 at 29-31 at § “Design of animal experiment”). This is pertinent because the prior art is replete with guidance identifying that MSCs alone, without introduction of a viral vector encoding instant SEQ ID NO: 2, are predicted and expected to treat inflammatory diseases:
Newman et al.9 pertains to the treatment of inflammatory diseases with mesenchymal stem cells circa 2009 (see, e.g., id. at title, abs). Newman identifies that the treatment of inflammatory diseases utilizing human mesenchymal stem cells was known in the art circa 2009, and therefore inflammatory diseases would have been predicted and expected to be successfully treated upon administration of MSC without introducing exogenous DNA sequences with viral vectors (see, e.g., Newman at 110 at col I-II at § Introduction, Fig. 1 on 112, Table 1 on 113, Table 2 on 114, 118 at col II at § VI “Human MSC Clinical Trials for Inflammatory Diseases”).
Regmi et al.10 pertains to mesenchymal stem cell therapy for the treatment of inflammatory diseases (see, e.g., Regmi at title, abs, 2 at col I at 1st full ¶, Fig. 2 on p.3, Fig. 3 on 4, 7 at § 4. “Application of MSC in inflammatory diseases”, Table 3 at 9, 10-11 at § 5.2 Genetic modification of stem cells, 12-13 at bridging ¶, passim).
Eljarrah et al.11 pertains to the therapeutic potential of Mesenchymal Stem Cells (including UCM-MSCs) in Immune-Mediated Diseases, including inflammatory disease (see, e.g., Eljarrah at title, abs, 97 at §§ 5.2.5, 98 at §§ 5.2.8, 98-99 at § 5.3, 101 at § 5.6).
US 20130028873 A1 teaches and claims methods of using mesenchymal stem cells originating from human umbilical cord-blood (UC-MSCs) (see, e.g., US’873 at claims 1 and 5) to suppress inflammatory reactions or to treat inflammation caused by a pulmonary disease (see, e.g., US’873 at claims 8-9, 11, 17) and cartilage injury diseases (see, e.g., US’873 at ¶[0136]). Accordingly, treating inflammation by administering UC-MSCs was known in the prior art, and would be predicted and expected to achieve treatment of inflammation without introducing exogenous DNA sequences with viral vectors.
US 20160151420 A1 teaches and claims a method for treating liver fibrosis or liver cirrhosis by administering MSCs to a patient (see, e.g., US’420 at claim 3), wherein liver fibrosis is understood to be characterized by “acute inflammation”, wherein live tissue is in a state of chronic inflammation (see, e.g., US’420 at ¶¶[0005]-[0006]). Accordingly, administration of MSCs to a patient would have been predicted and expected to treat inflammatory diseases without introducing exogenous DNA sequences with viral vectors.
US 20200011855 A1 teaches and claims a method for treating liver fibrosis or liver cirrhosis by administering MSCs to a patient (see, e.g., US’855 at claims 8 and 10), wherein liver fibrosis is understood to be characterized by “acute inflammation”, wherein live tissue is in a state of chronic inflammation (see, e.g., US’855 at ¶¶[0002], [0049]). Accordingly, administration of MSCs to a patient would have been predicted and expected to treat inflammatory diseases without introducing exogenous DNA sequences with viral vectors.
Kim et al.12, pertains to the usage of human MSCs to treat rotator cuff injuries (i.e., tendon repair), and discloses that circa 2017 it was known that MSC administration could be utilized to “significantly improve” outcomes (see, e.g., Kim at title, abs, passim).
Hernigou et al.13, pertains to methods of rotator cuff repair known circa 2014, comprising administering mesenchymal stem cells (MSCs) during arthroscopy, which was reported to improve healing and prevent further tears (see, e.g., Hernigou at title, abs, passim).
Pascual-Garrido et al.14, pertains to the treatment of chronic patellar tendinopathy with autologous bone marrow stem cells circa 2011, wherein treatment showed statistically significant improvement (see, e.g., Pascual-Garrido at title, abs, passim).
Accordingly, the utility of MSCs in the treatment of inflammatory diseases and tendon injuries was well-known in the prior art, and would be predicted and expected to occur. However, it is unclear what amounts of any other substance, in the absence of MSCs, would be necessary or sufficient to treat, in vivo, any inflammatory disorder presently claimed. This is relevant because the only proffered evidence of record comparing MSCs with MSCs with an AVV-Zkscan8 is shown at Figures 11(a)-11(e), but such data is of questionable statistical and practical difference:
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The error bars presumably represent “mean ± standard error (S.E.M.)”, but critically, the “MSC” and “MSC-Zk8” samples appear to substantially overlap (see, e.g., instant Figures 11(a)-(e)). This is pertinent because when error bars representing the standard error of the mean (S.E.M.) overlap and the sample sizes are equal, then the difference is not statistically significant (see, e.g., Krzywinski et al.15 at Fig. 1(a)-(b) and Fig. 2(b) at 921, Fig. 3 on 922, 921 at col II at 1st to 3rd full ¶¶, explaining that when S.E.M. bars touch with an n of 10, the P value is ~0.17, and for a P value of 0.05 or less, the error bars would need to be “about 0.86 lengths apart”). Accordingly, the proffered data appears to show the exact results expected and predicted in view of the prior art, namely that MSC can be administered to predictably treat inflammation, but no statistically significant effect of MSC-Zk8 relative to MSC is shown in vivo on record. Accordingly, it is unclear what extra effect can be obtained with Zkscan8 proteins or nucleotides in the absence of MSC as presently claimed.
This lack of statistically significant effect of MSC-Zk8 relative to MSC in vivo would be readily attributed to the known and art-recognized functionality of MSC cells (see bulleted list of references above, noting that the list is non-exhaustive). This raises a substantial question, namely, what does the Zkscan8 portion contribute in vivo if the proffered data confirms the expected and predicted results of the prior art? The proffered data of record does not clearly and unambiguously support a conclusion that the proffered results would be obtainable in the absence of the known effects of MSC cells. Therefore, an artisan would not reasonably conclude applicant possessed a method of treating diseases and disorders using a “therapeutically effective amount” of any component in the absence of MSC cells or MSC-derived extracellular vesicles in the absence of a supporting description and disclosure.
This distinction is pertinent because Zkscan8 of SEQ ID NO: 2 is a naturally occurring protein, and numerous prior art methodologies therefore exist wherein cells or cellular matter comprising human DNA is administered to humans in order to obtain a result (see, e.g., Coyle et al.16 at title, abs, noting that placentophagy, wherein a placenta is eaten raw, has been documented in humans; note that SEQ ID NO: 2 is a naturally occurring peptide and therefore the gene is naturally present in human placental cells). Such compositions appear to contain linear DNA encoding SEQ ID NO: 2, but do not acknowledge or attribute any activity to the presence of ZKscan8 protein. It is unclear if such prior art anticipates the instant claims or is excluded by the functionally defined term “administering”.
Predictability in the Art
Although the level of skill in the art is high, the predictability in the clinical arts is low due to the complexity of biological systems, differences in patient populations, differences in concentration effects, administration route effects, dosage frequency effects, and arbitrary metrics defining successful treatment among artisans. Specifically, an artisan would not be able to predict or identify, a priori, and in the absence of any guidance, the minimal, common structures, and “effective” concentrations, of compounds capable of successfully “treating” vastly different conditions of inflammatory diseases and conditions, wherein such compounds may lack MSC, SEQ ID NOs: 1-2, and may include unknown small molecule products (“culture”). Accordingly, in the absence of clear guidance regarding the functional definitions of proteins, genes, “cultures”, and what constitutes a “therapeutically effective amount” of compositions lacking MSCs, an artisan would not reasonably be able to predict or distinguish functional or infringing embodiments from non-functional or non-infringing embodiments.
Lack of Ability to Distinguish Infringing from Non-Infringing Embodiments
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 (i.e., exact peptide, polynucleotide, or small molecule structures) do or do not satisfy the functional limitations of claim 1, or otherwise identify what amount of a compound in the absence of MSCs is “therapeutically effective”, an artisan would be unable to identify infringing from non-infringing methods. Therefore, Applicant cannot lay claim to the instant subject matter.
Conclusion
The courts have held that a claim to a therapeutic method requiring administration of an “effective” amount of a compound at specific dosage range set forth in the disclosure for the treatment of a broad array of disorders failed to satisfy the Written Description Requirement because the disclosure addressed only “basic research and broad []dosage ranges”, but did not establish possession of a “therapeutically effective [] dose at the time of filing” (see, e.g., Biogen Int'l GmbH v. Mylan Pharm. Inc., 18 F.4th 1333, 1343, 2021 U.S.P.Q.2d 1170, 2021 BL 455178, at *8 (Fed. Cir. 2021). The court clarified that although
An inventor need not "prove that a claimed pharmaceutical compound actually achieves a certain result. But when the inventor expressly claims that result, our case law provides that [such] result must be supported by adequate disclosure in the specification.”
See Biogen Int'l GmbH v. Mylan Pharm. Inc., 18 F.4th 1333, 1343 (Fed. Cir. 2021).
The court further explained that
That Biogen later established the therapeutic efficacy of [a known compound at a specific dosage] is of no import to the written-description analysis. What matters for purposes of the inquiry [*1344] in this case is whether, at the time of filing the disclosure—well before the Phase III study even commenced—a skilled artisan could deduce simply from reading the specification that [a known compound at a specific dosage] would be a therapeutically effective treatment for MS. As to this point, the specification's focus on drug discovery and basic research further buttresses the district court's conclusion that the specification lacks an adequate written description to support the [] claims. . . . the law is clear that a patent cannot be awarded for mere theoretical research without more, see Ariad, 598 F.3d at 1353 . The written-description requirement limits patent protection only to individuals who perform the difficult work of producing a complete and final invention featuring all its claimed limitations and publicly disclose the fruits of that effort.
See Biogen Int'l GmbH v. Mylan Pharm. Inc., 18 F.4th 1333, 1344, 2021 U.S.P.Q.2d 1170, 2021 BL 455178, at *9 (Fed. Cir. 2021); emphasis added
Here, like in Biogen, the Specification is directed to basic research without clear clinical data sharing a nexus with the claims because zero embodiments of the claimed invention were actually reduced to practice or discussed with specificity in the absence of MSCs. Furthermore, unlike Biogen, here the claims further attempt to draw a fence around the treatment of all possible species of inflammatory diseases, using all possible “effective” concentrations, via all possible routes of administration, in all possible patient populations, of compositions not even sharing the structure of instant SEQ ID NOs:1 or 2. Therefore, the instant claims are substantially broader in scope than the claims of Biogen, but the disclosure of the instant Specification appears to provide substantially less guidance than that of the specification at issue in Biogen. Therefore, like Biogen, the instant claims lack written description support because an artisan “simply from reading the specification” could not deduce which compound at what concentration would be “effective” for the treatment of any particular inflammatory condition, as presently claimed.
Accordingly, claims 1-4 and 6-11 are rejected.
Applicant may potentially address the majority of the rejection by limiting the claim scope to include and require a UC-MSC modified with an AVV encoding SEQ ID NO: 2, and to the limit the claim scope to the treatment of tendon defects via local injection.
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, 6, and 11 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Coyle et al.17 as evidenced by NP_001265048.118 and as evidenced by Armstrong19.
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and those interpretations are incorporated into the instant rejection. For purposes of the instant rejection, the patient population “in need of” treatment includes patients at risk of inflammatory diseases (i.e., prophylactic treatment) (see, e.g., Spec. filed 1/25/2023 at 7, describing “prophylactically effective amount” for treatments). For purposes of the instant rejection, “administering” is deemed satisfied by administration of any amount of “Zkscan8 gene” wherein a therapeutic benefit is claimed or observed. Additional claim interpretations are set forth below.
Regarding instant claims 1, 3, and 11, and oral administration of raw human placental cells for the treatment of “inflammation” and other benefits, Coyle discloses that the practice of consuming raw placenta was practiced by human women “for the prevention of postpartum depression (PPD), pain relief, and other health benefits” including “increased milk production and energy”, “reduction of postpartum bleeding, more rapid uterine recovery, …and boosting of the immune system”, as well as “treating insomnia and other sleep disorders, inflammation and scars…”, etc. circa 2014 and earlier (see, e.g., Coyle at title, abs, 673-674 at bridging ¶, emphasis added; see also id. at 675 at col II, discussing anthropological evidence regarding maternal placentophagy). The amount of all naturally occurring substances present in such placental tissues is understood to be present in a “therapeutically effective amount” sufficient to achieve the predicted and expected benefits taught and discussed by Coyle (see id).
Regarding instant claims 1, 3, and a patient population “in need” of prophylactic treatment of inflammatory diseases, Coyle pertains to post-partum women (see, e.g., Coyle at title, abs, 673-674 at bridging ¶). Armstrong is cited herein to evidence that post-partum women are an art-recognized patient population that is at-risk of developing inflammatory diseases, including Crohn’s disease, colitis, and rheumatoid arthritis (see, e.g., Armstrong at 2 at 1st to 3rd ¶¶, 3 at final ¶ to 4 at final ¶). Accordingly, post-partum women, as treated in the primary reference are necessarily and inherently a patient population at-risk of developing inflammatory diseases, and therefore are understood to satisfy instant claim 1 because the Coyle patient population is “in need” of prophylactic treatment for inflammatory diseases.
Regarding instant claim 1-2, 6, and a “Zkscan8 gene”, “wherein the ZKscan8 is represented by” SEQ ID NO: 2, and a vector comprising “linear DNA”, Coyle pertains to administering placental cells (including raw) to post-partum women (see, e.g., Coyle at title, abs, 673-674 at bridging ¶), and the placental cells are vectors comprising linear, heterologous DNA that is delivered to the mother: Consumption of placental cells would inherently include administration of human genes from placental cells (i.e., containing fetal DNA) to the mother (i.e., mother receives heterologous DNA upon placental consumption), which would include the gene encoding and “represented by” instant SEQ ID NO: 2, which is a naturally-occurring human gene (see, e.g., NP_001265048 at § Definition on 1, and § References at 1-2; compare id. at sequence with instant SEQ ID NO: 2, showing 100% identity), and therefore the placental cells act as a vector comprising linear heterologous DNA, which is delivered to the mother upon consumption.
Regarding the “wherein” clause at claim 11, the “wherein” clause at claim 11 is reasonably deemed to be inherently satisfied by the administration of any amount of a “Zkscan8 gene” in a formulation taught and disclosed as sufficient to produce any therapeutic outcome. 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”. Here, the “wherein” clause does not unambiguously correspond to a clear structure/function relationship in the original disclosure, and therefore is not a functional limitation. Rather, the “wherein” clause is understood to merely recite an intended or expected result fully satisfied by any prior art that performs the positively recited steps and/or structures set forth in the body of the claim. Therefore, the “wherein” clause of claim 11 is understood to inherently and necessarily fully satisfied by the methodologies of placental consumption taught by Coyle, absent objective evidence to the contrary showing that the full scope of instant claim 1 is not enabled to satisfy the “wherein” clause.
Accordingly, claims 1-3, 6, and 11 are anticipated by the prior art.
Claims 1, 3-4, 6, and 8-11 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by WO2018/130554A1 (19 July 2018; Gimona et al.) as evidenced by NP_001265048.120.
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and those interpretations are incorporated into the instant rejection. For purposes of the instant rejection, “administering” is deemed satisfied by administration of any amount of “Zkscan8 gene” wherein a therapeutic benefit is claimed or observed. Additional claim interpretations are set forth below.
Regarding instant claims 1, 3-4, and the treatment of surgery-induced tendon defect (representative of tendinitis) by administering “a culture of” an umbilical cord-derived human mesenchymal stem cell, WO’554 teaches and reduces to practice a method of administering 10E6 equivalents of extracellular-vesicles derived from human Umbilical-cord derived MSC (“UC-MSC”) to a surgically-induced model for the “treatment of tendon defects”, wherein the model included rats receiving a “dermal punch” into a tendon, wherein the “cartilaginous enthesis was thoroughly removed using the punch in order to thoroughly destroy the tendon insertion site” (see, e.g., WO’554 at 56-57 at § 2.2, 86 at § Patellar tendon enthesis defect model; compare id. with Elected species at Spec. filed 1/25/2023 at 29 at § “Design of animal experiment”, noting that the elected species is an animal model for tendon injury, made by using a biopsy punch at the supraspinatus tendon and humeral head). The animal model of WO’554 is understood to be representative of “tendon defects” (see, e.g., WO’554 at 86 at § Patellar tendon enthesis defect model), wherein “tendon defects” include tendinitis, tendonitis, tendinosis, paratendinitis, peritendinitis, diseases and/or disorders of the synovitis and tenosynovitis, etc. (see, e.g., WO’554 at 33 at final ¶; compare id. with instant claims 1, 3-4).
Regarding instant claims 1-2, 6, 8-9, and “a culture of” a “cell comprising” a “linear DNA” encoding instant SEQ ID NO: 2, wherein the cell is a human umbilical cord-derived mesenchymal stem cell, WO’554 teaches and reduces to practice a method of administering 10E6 equivalents of extracellular-vesicles derived from human Umbilical-cord derived MSC (“UC-MSC”) to a surgically-induced model for the “treatment of tendon defects” (see, e.g., WO’554 at 44-45 at bridging ¶, 56-57 at § 2.2, 86 at § Patellar tendon enthesis defect model, 33 at final ¶). Critically, human cells, including the UC-MSC of WO’554 comprise linear DNA represented by instant SEQ ID NO: 2, which is a naturally-occurring human gene (see, e.g., NP_001265048 at § Definition on 1, and § References at 1-2; compare id. at sequence with instant claim 2 and instant SEQ ID NO: 2, showing 100% identity). Therefore, the UC-MSC cell culture products administered to rats are understood to be derived from UC-MSC cells that necessarily and inherently comprise and/or act as a vector as claimed (i.e., linear heterologous DNA encoding Zkscan8).
Regarding instant claim 1, and “a culture of the cell as an active ingredient”, the phase “a culture of the cell as an active ingredient” has been rejected as indefinite. For the instant rejection, the phrase is understood to be satisfied by any isolatable components present in a culture of UC-MSC cells that comprise linear DNA corresponding to instant SEQ ID NO: 2. Notably, WO’554 identifies, claims, and disclosed the usage of UC-MSC extracellular-vesicles to treat tendon defects, including tendinitis and peritendinitis (see, e.g., WO’554 at title, abs, 33 at final ¶, 44-45 at bridging ¶, claims 1-2, 32-33), wherein “extracellular vesicles” are understood to be derived as a culture product of MSCs (see, e.g., WO’554 at p. 3 at final ¶, 9-10 at bridging ¶, claim 43).
Regarding claim 1 and “administering”, 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)), which includes the administration and treatment of “tendon defects” in a surgical rat model using a culture product (i.e., extracellular vesicles) from human UC-MSC (see, e.g., WO’554 at 56-57 at § 2.2, 86 at § Patellar tendon enthesis defect model), wherein such amount is understood to be a “therapeutically effective amount” because it results in a reported benefit (see, e.g., WO’554 at 86-87 at § Patellar tendon enthesis defect model, 87 at Table 5).
Regarding the “wherein” clause at claim 11, the “wherein” clause at claim 11 is reasonably deemed to be inherently satisfied by the administration of any amount of a “Zkscan8 gene” in a formulation taught and disclosed as sufficient to produce any therapeutic outcome. 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”. Here, the “wherein” clause does not unambiguously correspond to a clear structure/function relationship in the original disclosure, and therefore is not a functional limitation. Rather, the “wherein” clause is understood to merely recite an intended or expected result fully satisfied by any prior art that performs the positively recited steps and/or structures set forth in the body of the claim. Therefore, the “wherein” clause of claim 11 is understood to inherently and necessarily fully satisfied by the methodologies of WO’554, absent objective evidence to the contrary showing that the full scope of instant claim 1 is not enabled to satisfy the “wherein” clause. This conclusion is supported by WO’554, which explains that the extracellular vesicles utilized result in gene expression levels indicative of “effective suppression of inflammation” (see, e.g., WO’554 at 7 at penultimate ¶; see also id. at 31 at penultimate ¶, 32 at 1st full ¶ starting with “Transplantation”).
Accordingly, claims 1, 3-4, 6, and 8-11 are anticipated by the prior art.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-4 and 6-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 10-15 of copending Application No. 18/007182 (reference application; corresponding to US 20230235402 A1) as evidenced by NP_001265048.121.
MPEP § 804(II)(B)(2)-(3) identifies that a Nonstatutory Double Patenting Rejection may be appropriate based upon either an anticipation analysis or an obviousness analysis (see, e.g., MPEP § 804(II)(B)(2)-(3)). Here, although the claims at issue are not identical, they are not patentably distinct from each other because both copending claim sets are directed to the treatment of inflammatory diseases (e.g., a tendon injury) by administering an umbilical cord-derived mesenchymal stem cell modified with a vector encoding a Zkscan8 gene or protein (compare instant claims 1, 3-4, and 6-11 with App’182 at claims 10-15). Although the claims of App’182 do not explicitly recite instant SEQ ID NO: 8, NP_001265048.1 evidences that it is art-recognized as “ZKscan8” and therefore the claims of the copending application necessarily and inherently encompass the same sequence, wherein administering the same composition to the same patient population would be expected to yield the same results (see, e.g., instant claims 1-2, 11; see App’181 at wherein clause at claim 10).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-2 and 6-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 5-6 of copending Application No. 18/842754 (reference application; corresponding to US 20250387433 A1) as evidenced by NP_001265048.122.
MPEP § 804(II)(B)(2)-(3) identifies that a Nonstatutory Double Patenting Rejection may be appropriate based upon either an anticipation analysis or an obviousness analysis (see, e.g., MPEP § 804(II)(B)(2)-(3)). Here, although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets are understood to be directed towards the treatment of inflammatory diseases and disorder by administering human-derived mesenchymal stem cells (or culture thereof) (compare id. at claims 1 and 6-11 with App’754 at claims 1-2 and 5-6). Although App’754 ostensibly is directed to retinal degenerative diseases (see, e.g., App’754 at claims 1 and 5), the term “retinal degenerative diseases” includes inflammation (see, e.g., App’754 at Spec. filed 5/5/2025 at [3]; per MPEP § 804(II)(B)(1), it is permissible to use the specification as a dictionary to learn the meaning of a term in a claim). Although App’754 does not explicitly recite a cell comprising a linear DNA encoding instant SEQ ID NO: 2, App’754 encompasses the administration of a human-derived MSC (or culture thereof) to patients, and NP_001265048.1 evidences that human-derived MSC would inherently encompass linear DNA encoding the naturally occurring protein at issue. Accordingly, the copending claim sets, although ostensibly directed to different treatments, are not patentably distinct because both copending claim sets read upon the treatment of patients in need of treatment for an inflammatory disease by administering a human MSC (or culture thereof) comprising and encoding natural human proteins, including instant SEQ ID NO: 2.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-4 and 6-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 7-12 of copending Application No. 18/034110 (reference application; corresponding to US 20230398156 A1).
MPEP § 804(II)(B)(2)-(3) identifies that a Nonstatutory Double Patenting Rejection may be appropriate based upon either an anticipation analysis or an obviousness analysis (see, e.g., MPEP § 804(II)(B)(2)-(3)). Here, although the claims at issue are not identical, they are not patentably distinct from each other because both copending claim sets are directed to the treatment of tendon or ligament diseases in subjects in need thereof (i.e., compare instant claims 3-4 with App’110 at claims 7 and 11, noting that at least tendinitis is listed for both), by administering to the subject an umbilical-cord derived MSC (i.e., compare instant claims 1 and 9-10 with App’110 at claim 7), that has been transduced with Zkscan8 of SEQ ID NO: 2 (i.e., compare instant claims 1-2 and 6-9 with App’110 at claim 7 and 9-10), wherein administering the same composition to the same patient population would be expected to yield the same results (see, e.g., instant claim 11; see App’110 at claims 8, 12).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
US20200063188A1 (see, e.g., US’188 at abs, ¶¶[0005], [0112], [0127], and Table 10), as the prior art teaches screens of ZKSCAN8 gene expression (see id), and it is well-within the ordinary skill in the art to assay gene expression before and after treatment to ascertain gene function.
US 10745759 discloses instant SEQ ID NO: 2 as SEQ ID NO: 38.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko G. Garyu can be reached at (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/RANDALL L BEANE/Primary Examiner, Art Unit 1654
1 NP_001265048.1, zinc finger protein with KRAB and SCAN domains 8 isoform 1 [Homo sapiens], GenPept, NCBI Reference Sequence: NP_001265048.1, NCBI, 3 pages, PRI 31-May-2019, also available at https://www.ncbi.nlm.nih.gov/protein/495529773?sat=47&satkey=111681244; last visited 4/29/2026; hereafter “NP_001265048”.
2 Registration number 3312539.
3 Registration number 1961415.
4 Serial number 75866375
5 Rost, Twilight zone of protein sequence alignments, Protein Engineering, vol. 12(2):85-94 (1999)
6 Coyle et al., Placentophagy: therapeutic miracle or myth? Arch Womens Ment Health. 2015 Oct;18(5):673-80. doi: 10.1007/s00737-015-0538-8. Epub 2015 Jun 4. PMID: 26043976; PMCID: PMC4580132.
7 Rost, Twilight zone of protein sequence alignments, Protein Engineering, vol. 12(2):85-94 (1999)
8 NP_001265048.1, zinc finger protein with KRAB and SCAN domains 8 isoform 1 [Homo sapiens], GenPept, NCBI Reference Sequence: NP_001265048.1, NCBI, 3 pages, PRI 31-May-2019, also available at https://www.ncbi.nlm.nih.gov/protein/495529773?sat=47&satkey=111681244; last visited 4/29/2026; hereafter “NP_001265048”.
9 Newman et al., Treatment of inflammatory diseases with mesenchymal stem cells. Inflamm Allergy Drug Targets. 2009 Jun;8(2):110-23. doi: 10.2174/187152809788462635. PMID: 19530993; hereafter “Newman”.
10 Regmi et al., Mesenchymal stem cell therapy for the treatment of inflammatory diseases: Challenges, opportunities, and future perspectives. Eur J Cell Biol. 2019 Dec;98(5-8):151041. doi: 10.1016/j.ejcb.2019.04.002. Epub 2019 Apr 14. PMID: 31023504; hereafter “Regmi”.
11 Eljarrah et al., Therapeutic Potential of Mesenchymal Stem Cells in Immune-Mediated Diseases. Adv Exp Med Biol. 2019;1201:93-108. doi: 10.1007/978-3-030-31206-0_5. PMID: 31898783; hereafter “Eljarrah”.
12 Kim et al., Does an Injection of Adipose-Derived Mesenchymal Stem Cells Loaded in Fibrin Glue Influence Rotator Cuff Repair Outcomes? A Clinical and Magnetic Resonance Imaging Study. Am J Sports Med. 2017 Jul;45(9):2010-2018. doi: 10.1177/0363546517702863. Epub 2017 Apr 27. PMID: 28448728.
13 Hernigou et al., Biologic augmentation of rotator cuff repair with mesenchymal stem cells during arthroscopy improves healing and prevents further tears: a case-controlled study. Int Orthop. 2014 Sep;38(9):1811-8. doi: 10.1007/s00264-014-2391-1. Epub 2014 Jun 7. PMID: 24913770.
14 Pascual-Garrido et al., Treatment of chronic patellar tendinopathy with autologous bone marrow stem cells: a 5-year-followup. Stem Cells Int. 2012;2012:953510. doi: 10.1155/2012/953510. Epub 2011 Dec 18. PMID: 22220180; PMCID: PMC3246763.
15 see, e.g., Krzywinski et al., Points of significance: error bars. Nat Methods. 2013 Oct;10(10):921-2. doi: 10.1038/nmeth.2659. PMID: 24161969; hereafter “Krzywinski”.
16 Coyle et al., Placentophagy: therapeutic miracle or myth? Arch Womens Ment Health. 2015 Oct;18(5):673-80. doi: 10.1007/s00737-015-0538-8. Epub 2015 Jun 4. PMID: 26043976; PMCID: PMC4580132.
17 Coyle et al., Placentophagy: therapeutic miracle or myth? Arch Womens Ment Health. 2015 Oct;18(5):673-80. doi: 10.1007/s00737-015-0538-8. Epub 2015 Jun 4. PMID: 26043976; PMCID: PMC4580132.
18 NP_001265048.1, zinc finger protein with KRAB and SCAN domains 8 isoform 1 [Homo sapiens], GenPept, NCBI Reference Sequence: NP_001265048.1, NCBI, 3 pages, PRI 31-May-2019, also available at https://www.ncbi.nlm.nih.gov/protein/495529773?sat=47&satkey=111681244; last visited 4/29/2026; hereafter “NP_001265048”.
19 Armstrong, “Autoimmune Disease After Pregnancy”, Rootfunctionalmedicine.com, 12 pages (Aug. 18, 2019), attached as pdf, also available at https://rootfunctionalmedicine.com/autoimmune-disease-after-pregnancy (last visited 4/29/2026).
20 NP_001265048.1, zinc finger protein with KRAB and SCAN domains 8 isoform 1 [Homo sapiens], GenPept, NCBI Reference Sequence: NP_001265048.1, NCBI, 3 pages, PRI 31-May-2019, also available at https://www.ncbi.nlm.nih.gov/protein/495529773?sat=47&satkey=111681244; last visited 4/29/2026; hereafter “NP_001265048”.
21 NP_001265048.1, zinc finger protein with KRAB and SCAN domains 8 isoform 1 [Homo sapiens], GenPept, NCBI Reference Sequence: NP_001265048.1, NCBI, 3 pages, PRI 31-May-2019, also available at https://www.ncbi.nlm.nih.gov/protein/495529773?sat=47&satkey=111681244; last visited 4/29/2026; hereafter “NP_001265048”.
22 NP_001265048.1, zinc finger protein with KRAB and SCAN domains 8 isoform 1 [Homo sapiens], GenPept, NCBI Reference Sequence: NP_001265048.1, NCBI, 3 pages, PRI 31-May-2019, also available at https://www.ncbi.nlm.nih.gov/protein/495529773?sat=47&satkey=111681244; last visited 4/29/2026; hereafter “NP_001265048”.
Prosecution Insights