Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on March 9, 2026 has been entered.
Detailed Action
This action is in response to the papers filed March 9, 2026.
Amendments
Applicant's amendments, filed March 9, 2026, is acknowledged.
Applicant has cancelled Claims 1-8, 10, 12-13, 24, 26-27, and 29-30, amended Claims 9, 11, 14-15, 18, 20-23, and 28, and added new claims, Claims 31-82.
Claims 9, 11, 14-23, 25, 28, and 31-82 are pending.
Election/Restrictions
Applicant has elected without traverse the following species, wherein:
i) the alternative DNA target region SEQ ID NO is SEQ ID NO:24, as recited in Claims 1 and 29-30;
ii) the alternative F1-F6 zinc finger protein SEQ ID NO combination is SEQ ID NO’s: 43, 68, 83, 103, 44, and 125, as recited in Claims 8-9; and
iii) the alternative ZFP DNA helix recognition sequence is SEQ ID NO:144, as recited in Claim 28.
Newly submitted Claims 50-81 are directed to an invention that is independent or distinct from the invention originally claimed for the following reasons: the claims are directed to a non-elected alternative F1-F6 zinc finger protein SEQ ID NO combination.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, Claims 50-81 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
As discussed in the Office Action mailed August 13,2025, upon the allowance of a generic claim, applicant will be entitled to consideration of claims to additional species which are written in dependent form or otherwise require all the limitations of an allowed generic claim.
Claims 9, 11, 14-23, 25, 28, and 31-82 are pending.
Claims 50-82 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 9, 11, 14-23, 25, 28, and 31-49 are under consideration.
Priority
This application is a 371 of PCT/US2020/054148 filed on October 2, 2020. Applicant’s claim for the benefit of a prior-filed application provisional application 62/959,153, filed on January 9, 2020 and 62/909,496 field on October 2, 2019 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994)
The disclosure of the prior-filed application, Application No. 62/909,496 field on October 2, 2019, and 62/959,153, filed on January 9, 2020, fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
While the specification of ‘496 discloses the nucleic acid target sequences and corresponding ZFP F1-F6 DNA-binding recognition helix sequences (pg 19, Table 1), ‘496 fails to disclose the ZFP domains of SEQ ID NO’s recited in Claim 28.
‘153 suffers a similar deficiency.
Support for Claim 28 SEQ ID NO’s may be found in PCT/US2020/054148 filed on October 2, 2020 (Table 2, pgs 27-31).
Accordingly, the effective priority date of Claims 28 and 30 is granted as October 2, 2020.
If applicant believes the earlier applications provide support for this disclosure, applicant should point out such support with particularity by page and line number in the reply to this Action.
Priority
This application is a 371 of PCT/US2020/054148 filed on October 2, 2020. Applicant’s claim for the benefit of a prior-filed application provisional application 62/959,153, filed on January 9, 2020 and 62/909,496 field on October 2, 2019 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Support for instantly recited SEQ ID NO’s may be found in 62/909,496 field on October 2, 2019 (pg 19, Table 1).
Allowable Subject Matter
1. The following is a statement of reasons for the indication of allowable subject matter:
Claim 9 recites a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequences SEQ ID NO:43-68-83-103-44-125, which appears to be free of the prior art.
Claims 11, 14, 32, 34-35, 36-38, 41, and 45 are in condition for allowance, being dependent upon Claim 9.
Claim 28 recites SEQ ID NO:144, which appears to be free of the prior art.
Zhang et al (U.S. Patent 7,534,775) is closest prior art for having disclosed a fusion protein comprising a ZFP domain comprising an amino acid sequence (SEQ ID NO:69) that is 87% identical to instant SEQ ID NO:144, as shown below:
MAPKKKRKV---GVPAAMAERPFQCRICMRNFSRSDDLTRHIRTHTGEKPFACDICGRKF
||||||||| |||||||||||||||||||||||| |::|||||||||||||||||:||
MAPKKKRKVGIHGVPAAMAERPFQCRICMRNFSRSDHLSQHIRTHTGEKPFACDICGKKF
AQKFPRDSHTKIHT---GSQKPFQCRICMRNFSRSDHLTQHIRTHTGEKPFACDICGRKF
|: | :|||||| |||:||||||||||||||| |: ||||||||||||||||||||
ARSDVRKNHTKIHTGGGGSQRPFQCRICMRNFSRSDALSVHIRTHTGEKPFACDICGRKF
ADSANLSRHTKIHTGSQKPFQCRICMRNFSDRSNLSRHIRTHTGEKPFACDICGRKFADR
||:|| ::|||||||||||||||||||||| :|| |||||||||||||||||||||
ADNANRTKHTKIHTGSQKPFQCRICMRNFSRSDHLSTHIRTHTGEKPFACDICGRKFATS
TSLKWHTKIHLRQKDAARGSGGDAKSLTAWSRTLVTFKDVFVDFTREEWKLLDTAQQIVY
:: |||||||||||||||| ||||||||||||||||||||||||||||||||||||||
SNRTKHTKIHLRQKDAARGSGMDAKSLTAWSRTLVTFKDVFVDFTREEWKLLDTAQQIVY
RNVMLENYKNLVSLGYQLTKPDVILRLEKGEEPWLVEREIHQETHPDSETAFEIKSSV
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
RNVMLENYKNLVSLGYQLTKPDVILRLEKGEEPWLVEREIHQETHPDSETAFEIKSSV
Although the ZFP domain scaffold of Zhang et al is substantially similar (97% identical; 8 amino acid differences) to the ZFP domain scaffold of SEQ ID NO:144, the DNA-binding recognition helix sequences of Zhang et al (underlined) differ from the DNA-binding recognition helix sequences (bolded) present in instant SEQ ID NO:144, respectively.
Zhang et al disclose the ZFP binds a target sequence in a phospholamban (PLN) gene (e.g. col. 2, Summary).
However, dependent Claims 15-17, 18-23, 25, 28, 31, 33, 39-40, 42-44, and 46-49 suffer from Double Patenting, 35 U.S.C. 101 or 35 U.S.C. 112 issues. See discussion below.
Claim Objections
1. Claim 9 is objected to because of the following informalities:
As a first matter, the claim lacks the conjunction “and” prior to the third ‘wherein’ clause.
As a second matter, while the ‘wherein’ clauses are separated by line breaks, they are not indented. Where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation, 37 CFR 1.75(i). See MPEP §608.01(m).
Appropriate correction is required.
2. Claims 18 and 28 are objected to because of the following informalities:
While the ‘wherein’ clauses are separated by line breaks, they are not indented. Where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation, 37 CFR 1.75(i). See MPEP §608.01(m).
Appropriate correction is required.
3. Claim 21 is objected to because of the following informalities:
The claim is unnecessarily verbose, as lines 1-3, reciting functional properties, appear to be redundant to the ZFP fusion protein of Claim 9.
To the extent Applicant argues otherwise, see the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejection(s) below.
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
4. Claims 15-17 and 42-44 are rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101).
The claims recite host cells comprising the nucleic acid construct of Claim 9, wherein said cells are human cells, including human brain cells, or pluripotent stem cells, including embryonic stem cells.
Claim 18 recites, for example, that the host cell includes brains cells present in a human subject, said human brain cells being integrated into the human being and therefore being an inseparable part of the human itself. The scope of the claim, therefore, encompasses a human being, which is non-statutory subject matter.
Those of ordinary skill in the art have long-recognized that pluripotent stem cells, e.g. embryonic stem cells, are used to develop into an animal, including human being.
See also the He Jianjui controversy of 2018.
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432
780
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As such, the recitation of the limitation “isolated” before “host cell” would be remedial.
See 1077 O.G. 24, April 21, 1987.
Double Patenting
5. Claim 39 is objected to under 37 CFR 1.75 as being a substantial duplicate of Claim 38.
When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). It is axiomatic that the AAV viral vector of Claim 38 comprising the nucleic acid construct of Claim 9 is a ‘recombinant’ AAV viral vector, as recited in Claim 39. There is no such thing as a naturally-occurring, non-recombinant AAV viral vector comprising the nucleic acid construct of Claim 9.
Claim Rejections - 35 USC § 112
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.
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.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
6. Claims 31 and 47-48 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 9 has been amended to recite a nucleic acid construct encoding a fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125.
Claim 45 recites the fusion protein of Claim 9.
Claim 28 recites a fusion protein of Claim 9.
Claims 31 and 47-48 recite wherein the fusion protein represses expression of the SNCA gene by at least 40%, 75%, 90%, 95%, or 99% with no detectable off-target binding or activity.
Either the functional properties of Claims 31 and 47-48 are inherent properties that naturally flow from the positively recited fusion proteins [structures] of Claims 9, 28, and 45, respectively, per natural law of cell biology and chemistry, or they are not, and something [unrecited structure(s)] of the Claims 9, 28, and 45 fusion proteins must change.
To the extent the functional properties of Claims 31 and 47-48 are inherent properties that naturally flow from the positively recited fusion proteins [structures] of Claims 9, 28, and 45, respectively, per natural law of cell biology and chemistry, then the instant claims fail to further limit Claims 9, 28, and 45, respectively.
Furthermore, in regard to instant Claims 31 and 47-48, it is noted that the "wherein" clause does not recite any additional structure(s) of the Claims 9, 28, and 45, but simply states a characterization or conclusion of the results of the fusion proteins of Claims 9, 28, and 45.
Therefore, the "wherein" clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993) ("A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim."). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.").
'Even if such a phrase did hold patentable weight, the phrase would likely be rejected under 35 USC 112(b) for being indefinite because such a phrase would amount to a 'functional limitation' whereby one of ordinary skill in the art would essentially need to 'guess' what steps must occur in the claim, in addition to the positively-recited method steps, in order to result in 'wherein the....' (the 'intended result' phrase in the claim).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
See further discussion below in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejection.
7. Claim(s) 21-22, 31, and 47-49 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.
Claim 9 has been amended to recite a nucleic acid construct encoding a fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125.
Claim 45 recites the fusion protein of Claim 9.
Claim 28 recites a fusion protein of Claim 9.
Claim 21 recites wherein the fusion protein encoded by the nucleic acid construct of Claim 9 has the functional property of binding to the target region in the human SNCA gene.
Claims 31 and 47-48 recite wherein the fusion protein represses expression of the SNCA gene by at least 40%, 75%, 90%, 95%, or 99% with no detectable off-target binding or activity.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
Either the functional properties of Claim 21 is/are an inherent property that naturally flows from the positively recited fusion protein(s) [structures] of Claim 9, respectively, per natural law of cell biology and chemistry, or it is not, and something [unrecited structure(s)] of the Claim 9 fusion protein(s) must change.
Claim 21 recites wherein the fusion protein encoded by the nucleic acid construct of Claim 9 has the functional property of binding to the target region in the human SNCA gene.
The claim denotes that not all fusion protein(s) of Claim 9, respectively, necessarily and predictably have the functional properties recited in Claim 21.
To the extent the functional properties of Claim 21 is/are not inherent properties that naturally flow from the positively recited fusion protein(s) [structures] of Claim 9, respectively, then the instant claim is considered to lack adequate written description for failing to recite the structural changes of the fusion proteins that necessarily and predictably have the recited functional properties.
Either the functional properties of Claims 31 and 47-48 are inherent properties that naturally flow from the positively recited fusion proteins [structures] of Claims 9, 28, and 45, respectively, per natural law of cell biology and chemistry, or they are not, and something [unrecited structure(s)] of the Claims 9, 28, and 45 fusion proteins must change.
The claims denote that not all fusion proteins of Claims 9, 28, and 45, respectively, necessarily and predictably have the functional properties recited in Claims 31 and 47-48.
To the extent the functional properties of Claims 31 and 47-48 are not inherent properties that naturally flow from the positively recited fusion proteins [structures] of Claims 9, 28, and 45, respectively, then the instant claims are considered to lack adequate written description for failing to recite the structural changes of the fusion proteins that necessarily and predictably have the recited functional properties.
The claims fail to recite, and the specification fails to disclose, a structure/function nexus between a fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 and the thus-achieved corresponding degree of SNCA repression, be it 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 99%, respectively.
The claims fail to recite, and the specification fails to disclose, a first fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is able to repress SNCA gene expression by at least 10%, but is not able to repress SNCA gene expression by at least 40%, 50%, 60%, 70%, 80%, 90%, or 99%, respectively, as opposed to a second fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is able to repress SNCA gene expression by at least 20%, but is not able to repress SNCA gene expression by at least 40%, 50%, 60%, 70%, 80%, 90%, or 99%, respectively, for example.
The claims fail to recite, and the specification fails to disclose, a first fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is able to repress SNCA gene expression by at least 30%, but is not able to repress SNCA gene expression by at least 40%, 50%, 60%, 70%, 80%, 90%, or 99%, respectively, as opposed to a second fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is able to repress SNCA gene expression by at least 40%, but is not able to repress SNCA gene expression by at least 50%, 60%, 70%, 80%, 90%, or 99%, respectively, for example.
The claims fail to recite, and the specification fails to disclose, a first fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is able to repress SNCA gene expression by at least 40%, but is not able to repress SNCA gene expression by at least 50%, 60%, 70%, 80%, 90%, or 99%, respectively, as opposed to a second fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is able to repress SNCA gene expression by at least 50%, but is not able to repress SNCA gene expression by at least 60%, 70%, 80%, 90%, or 99%, respectively, for example.
The claims fail to recite, and the specification fails to disclose, a first fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is able to repress SNCA gene expression by at least 50%, but is not able to repress SNCA gene expression by at least 60%, 70%, 80%, 90%, or 99%, respectively, as opposed to a second fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is able to repress SNCA gene expression by at least 60%, but is not able to repress SNCA gene expression by at least 70%, 80%, 90%, or 99%, respectively, for example.
The claims fail to recite, and the specification fails to disclose, a first fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is able to repress SNCA gene expression by at least 70%, but is not able to repress SNCA gene expression by at least 80%, 90%, or 99%, respectively, as opposed to a second fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is able to repress SNCA gene expression by at least 90%, but is not able to repress SNCA gene expression by at least 95%, or 99%, respectively, for example.
The claims fail to recite, and the specification fails to disclose, how to transform or otherwise modify a first fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is not able to repress SNCA gene expression by at least 40%, into a second fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is now necessarily and predictably has the functional property of repressing SNCA by at least 40%, for example.
The claims fail to recite, and the specification fails to disclose, how to transform or otherwise modify a first fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is not able to repress SNCA gene expression by at least 40%, into a second fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is now necessarily and predictably has the functional property of repressing SNCA by at least 70%, for example.
The claims fail to recite, and the specification fails to disclose, how to transform or otherwise modify a first fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is not able to repress SNCA gene expression by at least 40%, into a second fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is now necessarily and predictably has the functional property of repressing SNCA by at least 80%, for example.
The claims fail to recite, and the specification fails to disclose, how to transform or otherwise modify a first fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is not able to repress SNCA gene expression by at least 40%, into a second fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is now necessarily and predictably has the functional property of repressing SNCA by at least 90%, for example.
The claims fail to recite, and the specification fails to disclose, a structure/function nexus between the amino acid sequence(s) of the fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 and the thus-achieved corresponding degree of detectable off-target binding or activity.
The claims fail to recite, and the specification fails to disclose, a first fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is able to repress SNCA gene expression by at least 40%, but has detectable off-target binding or activity, as opposed to a second fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is able to repress SNCA gene expression by at least 40%, and does not have detectable off-target binding or activity, for example.
The claims fail to recite, and the specification fails to disclose, a first fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is able to repress SNCA gene expression by at least 70%, but has detectable off-target binding or activity, as opposed to a second fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is able to repress SNCA gene expression by at least 70%, and does not have detectable off-target binding or activity, for example.
The claims fail to recite, and the specification fails to disclose, a first fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is able to repress SNCA gene expression by at least 80%, but has detectable off-target binding or activity, as opposed to a second fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is able to repress SNCA gene expression by at least 80%, and does not have detectable off-target binding or activity, for example.
The claims fail to recite, and the specification fails to disclose, a first fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is able to repress SNCA gene expression by at least 90%, but has detectable off-target binding or activity, as opposed to a second fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is able to repress SNCA gene expression by at least 90%, and does not have detectable off-target binding or activity, for example.
The claims fail to recite, and the specification fails to disclose, a first fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is able to repress SNCA gene expression by at least 99%, but has detectable off-target binding or activity, as opposed to a second fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is able to repress SNCA gene expression by at least 99%, and does not have detectable off-target binding or activity, for example.
The claims fail to recite, and the specification fails to disclose, how to transform or otherwise modify a first fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is able to repress SNCA gene expression by at least 40%, but has detectable off-target binding or activity, into a second fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is able to repress SNCA gene expression by at least 40%, and now necessarily and predictably has no detectable off-target binding or activity, for example.
The claims fail to recite, and the specification fails to disclose, how to transform or otherwise modify a first fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is able to repress SNCA gene expression by at least 70%, but has detectable off-target binding or activity, into a second fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is able to repress SNCA gene expression by at least 70%, and now necessarily and predictably has no detectable off-target binding or activity, for example.
The claims fail to recite, and the specification fails to disclose, how to transform or otherwise modify a first fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is able to repress SNCA gene expression by at least 80%, but has detectable off-target binding or activity, into a second fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is able to repress SNCA gene expression by at least 80%, and now necessarily and predictably has no detectable off-target binding or activity, for example.
The claims fail to recite, and the specification fails to disclose, how to transform or otherwise modify a first fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is able to repress SNCA gene expression by at least 90%, but has detectable off-target binding or activity, into a second fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is able to repress SNCA gene expression by at least 90%, and now necessarily and predictably has no detectable off-target binding or activity, for example.
The claims fail to recite, and the specification fails to disclose, how to transform or otherwise modify a first fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is able to repress SNCA gene expression by at least 99%, but has detectable off-target binding or activity, into a second fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 that is able to repress SNCA gene expression by at least 99%, and now necessarily and predictably has no detectable off-target binding or activity, for example.
Moreira et al (Hot spots—A review of the protein–protein interface determinant amino-acid residues, Proteins 68: 803-812, 2007; of record) is considered relevant prior art for having taught that protein–protein interactions are very complex and can be characterized by their size,
shape, and surface complementarity (e.g. pg 803, Protein-Protein). The hydrophobic and electrostatic interactions they establish, as well as the flexibility of the molecules involved, are very significant.
Moreira et al taught that in a protein–protein interface, a small subset of the buried amino acids typically contribute to the majority of binding affinity as determined by the change in the free energy of binding. Although there is no purely geometric reason, these energetic determinants are compact, centralized regions of residues crucial for protein association (e.g. pg 804, col. 2).
Moreira et al taught that most interfaces are optimal tight-fitting regions characterized by complementary pockets scattered through the central region of the interface, and enriched in structurally conserved residues. These pockets are classified as ‘‘complementary’’ because there is a large complementarity both in shape and in the juxtaposition of hydrophobic and hydrophilic hot spots, with buried charged residues forming salt bridges and hydrophobic residues from one surface fitting into small nooks on the opposite face. Usually, the hot spot of one face packs against the hot spot of the other face establishing a region determinant for complex binding (e.g. pg 806, col. 1). Complementarity is basically affected by the size of the buried surface, alignment of polar and nonpolar residues, number of buried waters, and the packing densities of atoms involved in the protein–protein interface. Packing defects at the protein–protein interface result in these gaps or pockets, and it is unclear whether unfilled pockets contain water molecules or how the dynamics of water molecules entering and escaping these pockets may affect binding stability (e.g. pg 807, col. 2). Moreira et al taught that common methodology to determine hot spot locations on the artisan’s protein of interest, alanine-scanning mutagenesis is slow and labor-intensive (e.g. pg 804, col. 1). Similarly, systematic mutagenesis is very laborious and time-consuming to perform, as individual mutant proteins must be purified and analyzed separately (e.g. pg 808, col. 2).
Ng et al (Predicting the Effects of Amino Acid Substitutions on Protein Function, Annual Review Genomics Human Genetics 7: 61-80, 2006; of record) is considered relevant prior art for having taught that non-synonymous nucleotide changes which introduce amino acid changes in the corresponding protein have the largest impact on human health. Most algorithms to predict amino acid substation consequences of protein function indicate about 25% to 30% of amino acid changes negatively affect protein function (Abstract). Existing prediction tools primarily focus on studying the deleterious effects of single amino acid substitutions through examining amino acid conservation at the position of interest among related sequences, an approach that is not directly applicable to multiple amino acid changes, including insertions or deletions. Ng et al taught that 83% of disease-causing mutations affect protein stability (e.g. pg 63, col. 1), which in this case, would affect the ability of the enormously vast genus of about 1x10^117 structurally and functionally undisclosed ZFP protein variants to necessarily and predictably have the functional properties of recognizing one or more structurally undisclosed nucleic acid target sequences in a human SNCA gene, let alone within 1000 and/or 500 nucleotides of the SNCA transcription start stie 1, 2a, and/or 2b.
Ng et al taught that while multiple sequence alignment of the homologous sequences reveals what positions have been conserved throughout evolutionary time, and these positions are inferred to be important for function (e.g. pg 63, col. 1), Users should be cautious even with proteins that are judged to be orthologous based on phylogeny. Orthologous genes in different species are derived from a common ancestor, but they may not necessarily have the same function. If function has changed, then amino acids that are important for the function of one protein may not necessarily be important for the function of the ortholog. 2% of disease-causing mutations in human genes are identical to the sequences of their respective mouse orthologs, suggesting that even though these positions have huge phenotypic effects on human health, they have different roles or are no longer important in mice If the orthologs in alignment have slightly different functions, then the positions that differentiate function among orthologs may be incorrectly predicted. (e.g. pg 68, col. 1). When there are many missense mutations in the gene(s) of interest, assaying all missense mutations, which introduce amino acid changes, can be expensive and time-consuming (e.g. pg 74, col. 1). Prediction accuracy has gradually improved, but few head-to-head comparisons exist. Moreover, as the number of servers providing AAS prediction increases, it will become increasingly difficult for investigators to interpret the predictions. (e.g. pg 74, col. 2). Ng et al taught that the error rate of functional annotations in the sequence database is considerable, making it even more difficult to infer correct function from a structural comparison of a new sequence with a sequence database (e.g. Table 1, error rates of about 40% to 60%).
Prediction of protein structure by homology and/or algorithm is notoriously difficult, as one of ordinary skill in the art would immediately understand.
Handel et al (Zinc-Finger Nuclease Based Genome Surgery: It’s All About Specificity, Current Gene Therapy 11: 28-37, 2011; of record) is considered relevant prior art for having taught that a key issue in the successful biotechnological and therapeutic applications of ZFPs is undeniably the specificity of the nucleases, which is closely linked to ZFP activity and ZFP-associated toxicity (e.g. pg 28, col. 2). The prior art has shown that the DNA binding specificity is a major factor governing ZFP activity and that specificity is inversely correlated with ZFP-associated toxicity (syn. off-target effects). ZFP subunits that do not contain a DNA-binding domain with sufficient affinity to the recognition site will either not find the DNA target at all or bind and cleave many similar sequences in the genome and therefore cause toxicity (pg 29). Determination of the in vivo specificity is quite challenging (pgs 29-30). While modular assembly strategy is appealing due to its straightforwardness, the price for this simplicity is the relatively low success frequency (below 10%) in terms of generating ZFPs that work in the context of a complex genome, and there is some concern about the specificities of such ZFPs. One reason for the low success rate may be that the zinc fingers in a multi-finger array are not truly modular, as individual zinc fingers in an array show positive and negative cooperativity in DNA binding (e.g. pg 33, col. 2). Irrespective of the platform used to assemble the zinc finger arrays, a burning issue with regard to specificity of ZFPs is the question about the optimal number of zinc finger motifs per ZFP subunit (e.g .pg 34, col. 1). For modular assembly, an optimal array seems to consist of 3 to 5 zinc finger modules, while a 6-finger ZFP subunit performed worse (e.g. pg 34, col. 1). Also, one should ask ‘what is the optimal affinity of a ZFP subunit?’ Undoubtedly, zinc finger arrays with little affinity will either bind DNA in a non-specific fashion, or not at all. The prior art taught an example whereby the activity of the three-finger ZFP E3 was barely detectable, while the six-finger ZFN E6 was only half as active as the corresponding ZFN E4 and E5 with four and five fingers, respectively (e.g. pg 34, col. 1). High affinity to the target site does not always translate into high specificity.
Juarez et al (Breaking through an epigenetic wall: Re-activation of Oct4 by KRAB-containing designer zinc finger transcription factors Epigenetics 8(2): 164-176, 2013; of record) is considered relevant prior art for having taught a designer fusion protein comprising a ZFP and a KRAB transcription repressor domain. Juarez et al taught that, while KRAB-containing ZFPs are traditionally described as transcriptional repressors, they found that these proteins can also function as potent transcriptional activators (Abstract), which is opposite of the functional property to be achieved by the instantly claimed invention. Juarez et al taught that the potency of the ZFP was dependent on the cell type, and the genomic microenvironment critically influences the regulatory outcome, be it transcriptional repression or transcriptional activation, of the KRAB-ZFPs (e.g. pg 165, col. 2).
Thus, simply appending the enormously vast genus of about 1x10^117 structurally and functionally undisclosed ZFP protein variants to a transcriptional repressor domain, including a KRAB domain, as recited in Claim 6, is not, in and of itself dispositive to necessarily and predictably yield the functional property of inhibiting expression of the SNCA gene.
The instantly recited host cells, including brain, pluripotent stem cells, embryonic stem cells, and induced pluripotent stem cells are each recited at a high level of generality, whereby those of ordinary skill in the art immediately recognize that the genomic microenvironment of brain cells, e.g. neurons, glial cells, astrocytes, ependymal cells, neuroepithelial cells, pluripotent stem cells, embryonic stem cells, and induced pluripotent stem cells are each structurally and functionally different, as each of these cell types have distinctly different cell differentiation status and gene transcriptome profiles.
Dansithong et al (Generation of SNCA Cell Models Using Zinc Finger Nuclease (ZFN) Technology for Efficient High-Throughput Drug Screening, PLoS ONE 10(8): e0136930, 19 pages, doi: 10.1371/journal.pone.0136930; available online August 28, 2015; of record) is considered relevant prior art for having taught that expression control of SNCA is complex, in part due to the great length of the SNCA promoter and transcriptional control elements located very far, i.e. 8800 nucleotides, upstream of the transcription start site (e.g. pg 2, para 2-3). Dansithong et al taught the construction of a ZFP that targets a site downstream of SNCA, e.g. within exon 6 (Figure 1).
The specification fails to make up for the deficiencies of the global scientific community.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function ... does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is’).
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
8. Claims 28, 33, 40, 46, and 48 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.
As a first matter, the claims recite the phrase “shown as”. The conjunctive adverb "as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
It is the Examiner’s position that the use of the term “as” renders the referenced SEQ ID NO merely as an example [emphasis added] and does not exclude other amino acid sequences encoding a fusion protein comprising a transcription repressor domain and a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequence SEQ ID NO’s: 43-68-83-103-44-125 (Claim 28), and does not exclude other amino acid sequences encoding a KRAB domain (Claim 33).
As a second matter, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, Claim 28 recites the broad recitation “an amino acid sequence shown as”, and the claim also recites “SEQ ID NO:144”, which is/are the narrower statement of the range/limitation. Claim 33 recites the broad recitation “an amino acid sequence shown as”, and the claim also recites “SEQ ID NO:12”, which is/are the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
As a third matter, the phrase “an amino acid sequence shown as SEQ ID NO…” renders the claim indefinite because the referenced SEQ ID NO is composed of a plurality of amino acid subsequences, respectively.
The Directors Technology Center 1600 Memorandum, Nucleic Acid and Peptide Claim Interpretation: “A” and “The” (December 29, 2005) informs the TC1600 Examiners that the phrase “A nucleic acid comprising a nucleotide sequence of SEQ ID NO:1” encompasses nucleic acids that comprise any portion of SEQ ID NO:1; whereas, the phrase “A nucleic acid comprising the nucleotide sequence of SEQ ID NO:1” is directed only to nucleic acids that comprise the full length of SEQ ID NO:1.
English has two articles: ‘the’, and ‘a/an’.
‘the’ is a definite article, referring to a specific or particular noun; whereas, ‘a/an’ is an indefinite article, modifying non-specific or non-particular nouns.
It is unclear to which subsequence “sequence shown as” the reference SEQ ID NO Applicant refers.
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
The Examiner suggests amending Claim 28 to recite “the amino acid sequence of SEQ ID NO:144”.
The Examiner suggests amending Claim 33 to recite “the amino acid sequence of SEQ ID NO:12”.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
9. Claim 19 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 18 has been amended to recite a method of inhibiting expression of alpha-synuclein in a human brain cell, comprising the step of administering via intravenous, or injection into any brain region, a vector comprising a polynucleotide sequence encoding the fusion protein of claim 9.
Claim 19 recites wherein the human brain cell is a neuron, a glial cell, an ependymal cell, or a neuroepithelial cell.
Either the target cells of Claim 19 are inherently genetically modified with the vector, per the positively recited administration routes of Claim 18, per natural law of anatomy, physiology, and biology, or they are not, and something [unrecited structure(s) and/or method step(s)] of independent Claim 18 must change.
To the extent the target cells of Claim 19 are inherently genetically modified with the vector, per the positively recited administration routes of Claim 18, per natural law of anatomy, physiology, and biology, then the instant claim fails to further limit the independent claim.
Furthermore, in regard to instant Claim 19, it is noted that the "wherein" clause does not recite any additional structure(s) and/or active method step(s) of the independent Claim 18, but simply states a characterization or conclusion of the results of the method of Claim 18.
Therefore, the "wherein" clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993) ("A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim."). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.").
'Even if such a phrase did hold patentable weight, the phrase would likely be rejected under 35 USC 112(b) for being indefinite because such a phrase would amount to a 'functional limitation' whereby one of ordinary skill in the art would essentially need to 'guess' what steps must occur in the claim, in addition to the positively-recited method steps, in order to result in 'wherein the....' (the 'intended result' phrase in the claim).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Response to Arguments
Applicant argues that the amendment to Claim 18 renders the rejection moot.
Applicant’s argument(s) has been fully considered, but is not persuasive. Applicant’s amendment to Claim 18 does nothing to address the issues of Claim 19.
Either the target cells of Claim 19 are inherently genetically modified with the vector, per the positively recited administration routes of Claim 18, per natural law of anatomy, physiology, and biology, or they are not, and something [unrecited structure(s) and/or method step(s)] of independent Claim 18 must change.
To the extent the target cells of Claim 19 are inherently genetically modified with the vector, per the positively recited administration routes of Claim 18, per natural law of anatomy, physiology, and biology, then the instant claim fails to further limit the independent claim.
Furthermore, in regard to instant Claim 19, it is noted that the "wherein" clause does not recite any additional structure(s) and/or active method step(s) of the independent Claim 18, but simply states a characterization or conclusion of the results of the method of Claim 18.
10. Claim(s) 19 is 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.
Claim 18 has been amended to recite a method of inhibiting expression of alpha-synuclein in a human brain cell, comprising the step of administering via intravenous, or injection into any brain region a vector comprising a polynucleotide sequence encoding the fusion protein of claim 1.
Claim 19 recites wherein the human brain cell is a neuron, a glial cell, an ependymal cell, or a neuroepithelial cell.
Either the target cells of Claim 19 are inherently genetically modified with the vector, per the positively recited administration routes of Claim 18, per natural law of anatomy, physiology, and biology, or they are not, and something [unrecited structure(s) and/or method step(s)] of independent Claim 18 must change.
The claim denotes that not all of the structures/method steps of the independent claim are able to achieve the functional property(ies) recited in the dependent claim(s).
To the extent the target cells of Claim 19 are not inherently genetically modified with the vector, per the positively recited administration routes of Claim 18, per natural law of anatomy, physiology, and biology, then something must change. The claim is considered to lack adequate written description for failing to recite the structure(s) and/or method step(s) that is/are necessary and sufficient to cause the recited functional language.
Furthermore, in regard to instant Claim 19, it is noted that the "wherein" clause does not recite any additional structure(s) and/or active method step(s) of the independent Claim 18, but simply states a characterization or conclusion of the results of the method of Claim 18.
The "wherein" clause does not recite any additional structure(s) and/or active method step(s) of the independent Claim 18, but simply states a characterization or conclusion of the results of the method of Claim 18 without providing any indication about how the functional characteristic is provided. The functional characteristic does not follow from (is not an inherent property of) the structure(s) and/or method step(s) recited in Claim 18, and thus the ordinary artisan would not know what modification(s) must be made in order to fulfill the instant recitation.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
The claims fail to recite, and the specification fails to disclose, a nexus between the required vector structure(s) and/or administration method step(s) of Claim 18 and the resulting functional properties of genetically modifying the target cells of Claim 19.
The claims fail to recite, and the specification fails to disclose, a first vector administered via a first administration route, e.g. intracerebroventricular injection, that is necessarily and predictably able to genetically modify a neuron in a human subject, as opposed to a second vector administered via a second administration route, e.g. intranigral injection, that is unable to genetically modify a neuron in a human subject, for example.
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not clarify the nature of the corresponding structure that is necessary and sufficient to cause the recited functional language.
Response to Arguments
Applicant argues that the specification discloses that the brain cell may be a neuron, glial cell, ependymal cell, or neuroepithelial cell.
Applicant’s argument(s) has been fully considered, but is not persuasive. Applicant’s argument is not on point.
Either the target cells of Claim 19 are inherently genetically modified with the vector, per the positively recited administration routes of Claim 18, per natural law of anatomy, physiology, and biology, or they are not, and something [unrecited structure(s) and/or method step(s)] of independent Claim 18 must change.
The claim denotes that not all of the structures/method steps of the independent claim are able to achieve the functional property(ies) recited in the dependent claim(s).
To the extent the target cells of Claim 19 are not inherently genetically modified with the vector, per the positively recited administration routes of Claim 18, per natural law of anatomy, physiology, and biology, then something must change. The claim is considered to lack adequate written description for failing to recite the structure(s) and/or method step(s) that is/are necessary and sufficient to cause the recited functional language.
Furthermore, in regard to instant Claim 19, it is noted that the "wherein" clause does not recite any additional structure(s) and/or active method step(s) of the independent Claim 18, but simply states a characterization or conclusion of the results of the method of Claim 18.
The "wherein" clause does not recite any additional structure(s) and/or active method step(s) of the independent Claim 18, but simply states a characterization or conclusion of the results of the method of Claim 18 without providing any indication about how the functional characteristic is provided. The functional characteristic does not follow from (is not an inherent property of) the structure(s) and/or method step(s) recited in Claim 18, and thus the ordinary artisan would not know what modification(s) must be made in order to fulfill the instant recitation.
11. Claims 21-22 and 49 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 21 recites the limitation “a recombinant virus” in reference to the pharmaceutical composition of Claim 14. There is insufficient antecedent basis for this limitation in the claim because the pharmaceutical composition of Claim 14 is not a recombinant virus. See, instead, Claim 41, for example.
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
The Examiner suggests amending Claim 18 to recite “the pharmaceutical composition of Claim 14 or a pharmaceutical composition comprising a viral vector comprising the nucleic acid construct of Claim 9”.
The Examiner suggests amending Claim 21 cancelling the redundant functional limitations of lines 1-3, and instead simply recite “wherein the pharmaceutical composition comprises a viral vector comprising the nucleic acid construct of Claim 9 and expresses the fusion protein”.
12. Claims 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.
It is understood that in order to meaningfully treat the subject, and thereby satisfy the requirements of 35 U.S.C. 101 (See MPEP 2107.01 III, Therapeutic or Pharmacological Utility), a therapeutically effective amount or dose of the nucleic acid molecules expressing the ZFP-TF polypeptides must be administered to the subject, thereby achieving some real-world, clinically meaningful effect, and thereby being of “immediate benefit to the public”.
The phrase “an effective amount” has been held to be indefinite when the claim fails to state the function which is to be achieved and more than one effect can be implied from the specification or the relevant art. In reFredericksen, 213 F.2d 547, 102 USPQ 35 (CCPA 1954). MPEP 2173.05(c)
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
The claims denote that there is an amount of the nucleic acid pharmaceutical that is not, in fact, ‘a therapeutically effective amount’ (syn. sub-therapeutic amount).
The claims denote that there is an amount of the nucleic acid pharmaceutical that, upon administration to the subject via intravenous route and/or injection into any brain region, is not, in fact, able to achieve a real-world, clinically meaningful treatment of a synucleinopathy in a human patient.
An “effective amount” and/or a “therapeutically effective amount” is a functional property that is dependent upon many different variable parameters, including, but not limited to:
the type of human or non-human animal subject to be treated [parameter 1];
the type of nucleic acid construct encoding said ZFN fusion protein and/or viral vector comprising said nucleic acid construct [parameter 2];
the dosage administered [parameter 3];
the administration route [parameter 4]; and
the therapeutic phenotype to be achieved [parameter 5].
Parameter 1
The claims are broad for reasonably encompassing an enormous genus of animal and mammalian subjects, including, but not limited to, a human, a veterinary or farm animal, a domestic animal or pet, and animals normally used for clinical research, murine, rat, canine, feline, porcine, bovine, ovine, non-human primate and others [0036].
The claims are broad for encompassing about 1,000,000 species of animals (Kingdoms of Life, waynesword.palomar.edu/trfeb98.htm, last visited April 8, 2021; of record), wherein the mammalian sub-genus reasonably encompasses some 6,400 species (including humans), distributed in about 1,200 genera, about 152 families and about 29 orders (Mammal, en.wikipedia.org/wiki/Mammal, last visited August 31, 2022; of record).
As discussed above, the Examiner notes that while it is clear the target cell of Claim 18 is a human brain cell, the claim fails to recite that the subject is a human subject (see, instead, Claim 23, “human patient”). Thus, the breadth of Claim 18 reasonably encompasses xenograft animal models comprising human brain cells.
Parameter 2
The breadth of the claimed nucleic acid constructs to be administered is enormously broad for encompassing double-stranded DNA, RNA, plasmids, cosmids, transposons, phages, and viral vectors. The specification discloses nucleic acid vectors at a high level of generality (e.g. [055]), e.g. including RNA, cDNA, or plasmids (e.g. [018, 55, 67]), whereby the nucleic acid may be administered to the patient in the form of a liposome (e.g. [055]) or viral vector (e.g [0057-58]).
The claims are broad for encompassing an enormous genus of at least 125 different AAV capsid serotype variants, including but not limited to, AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV.rh10, and BAAV (DiPrimio et al (U.S. 2009/0215879; Table 3).
Parameter 3
The breadth of the claimed dosages of the claimed nucleic acid constructs to be administered is enormously broad, as the independent claims fail to recite the minimal dosage of the broadly claimed vectors, recited at a high level of generality, that is to be administered to the human patient.
The claimed methods are recited at a high level of generality for the nucleic acid vector dosage that is to be administered, including, but not limited to, as little as 1x10^2 to 1x10^20 vector genomes, or more (e.g. Vetter et al (U.S. 2023/0103708, [0152]).
Parameter 4
The claimed methods are recited at a high level of generality for the multitude of anatomically distinct administration routes, including, but not limited to, delivery and administration systemically, regionally or locally by intravenous injection, infusion, intracranially, intra-spinal, intrathecal, intracerebroventricular, intra-cistemal magna, intrastriatal, or intranigral injection, or injection into any brain region.
Parameter 5
The claims are broad for reasonably encompassing an enormous genus of physiologically and phenotypically different results, which evokes the question: A therapeutically effective amount to do what?
The recitation implies a genus of unrecited and undisclosed phenotypes by which the therapeutically effective dose is to be determined and/or identified, thereby rendering the claim indefinite. A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
The specification discloses, for example:
i) slowing the progression of a synucleinopathy [013], whereby that which is/is not “slowing” is/are considered to be an arbitrary and subjective determination;
ii) alleviation of symptoms, [059], whereby that which is/is not “alleviation” is/are considered to be an arbitrary and subjective determination;
iii) prevention of one or more symptoms [059];
iv) improvement of quality of life [059], whereby that which is/is not “improvement” is/are considered to be an arbitrary and subjective determination; and
v) increased survival [059], whereby that which is/is not “increased survival” is/are considered to be an arbitrary and subjective determination given that there is no objective reference from which to measure said increased survival. There is only one human patient, who is either dead or alive. One cannot measure increased survival on the treated patient because said patient is no longer non-treated, from which to objectively measure “increased survival”.
If there are multiple ways to measure ‘therapeutically effective dose’ or ‘therapeutically effective amount’ and/or ‘effective amount’, to wit, dosage, time after administration, and/or phenotypic result, yet each yields a different result, then the claim may be indefinite because it is unclear which method is to be performed to determine infringement.
See further discussion below in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claims.
Appropriate correction is required.
13. Claim(s) 18-23, 25, and 49 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.
Claims 18 and 23 have been amended to recite methods of administering a pharmaceutical composition comprising the nucleic acid construct of Claim 9 to a human brain cell, the methods comprising the step of administering the nucleic acid pharmaceutical via an intravenous route or injection into any brain region of the subject (Claim 18), more specifically a human subject (Claim 23).
The Examiner notes that while it is clear the target cell of Claim 18 is a human brain cell, the claim fails to recite that the subject is a human subject (see, instead, Claim 23, “human patient”). Thus, the breadth of Claim 18 reasonably encompasses xenograft animal models comprising human brain cells.
The Examiner incorporates herein the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejection.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
It is understood that in order to meaningfully treat the subject, and thereby satisfy the requirements of 35 U.S.C. 101 (See MPEP 2107.01 III, Therapeutic or Pharmacological Utility), a therapeutically effective amount or dose of the nucleic acid molecules expressing the ZFP-TF polypeptides must be administered to the subject, thereby achieving some real-world, clinically meaningful effect, and thereby being of “immediate benefit to the public”.
The phrase “an effective amount” has been held to be indefinite when the claim fails to state the function which is to be achieved and more than one effect can be implied from the specification or the relevant art. In reFredericksen, 213 F.2d 547, 102 USPQ 35 (CCPA 1954). MPEP 2173.05(c)
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
The claims denote that there is an amount of the nucleic acid pharmaceutical that is not, in fact, ‘a therapeutically effective amount’ (syn. sub-therapeutic amount).
The claims denote that there is an amount of the nucleic acid pharmaceutical that, upon administration to the subject via intravenous route and/or injection into any brain region, is not, in fact, able to achieve a real-world, clinically meaningful treatment of a synucleinopathy in a human patient.
An “effective amount” and/or a “therapeutically effective amount” is a functional property that is dependent upon many different variable parameters, including, but not limited to:
the type of human or non-human animal subject to be treated [parameter 1];
the type of nucleic acid construct encoding said ZFN fusion protein and/or viral vector comprising said nucleic acid construct [parameter 2];
the dosage administered [parameter 3];
the administration route [parameter 4]; and
the therapeutic phenotype to be achieved [parameter 5].
Parameter 1
The claims are broad for reasonably encompassing an enormous genus of animal and mammalian subjects, including, but not limited to, a human, a veterinary or farm animal, a domestic animal or pet, and animals normally used for clinical research, murine, rat, canine, feline, porcine, bovine, ovine, non-human primate and others [0036].
The claims are broad for encompassing about 1,000,000 species of animals (Kingdoms of Life, waynesword.palomar.edu/trfeb98.htm, last visited April 8, 2021; of record), wherein the mammalian sub-genus reasonably encompasses some 6,400 species (including humans), distributed in about 1,200 genera, about 152 families and about 29 orders (Mammal, en.wikipedia.org/wiki/Mammal, last visited August 31, 2022; of record).
As discussed above, the Examiner notes that while it is clear the target cell of Claim 18 is a human brain cell, the claim fails to recite that the subject is a human subject (see, instead, Claim 23, “human patient”). Thus, the breadth of Claim 18 reasonably encompasses xenograft animal models comprising human brain cells.
Parameter 2
The breadth of the claimed nucleic acid constructs to be administered is enormously broad for encompassing double-stranded DNA, RNA, plasmids, cosmids, transposons, phages, and viral vectors. The specification discloses nucleic acid vectors at a high level of generality (e.g. [055]), e.g. including RNA, cDNA, or plasmids (e.g. [018, 55, 67]), whereby the nucleic acid may be administered to the patient in the form of a liposome (e.g. [055]) or viral vector (e.g [0057-58]).
The claims are broad for encompassing an enormous genus of at least 125 different AAV capsid serotype variants, including but not limited to, AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV.rh10, and BAAV (DiPrimio et al (U.S. 2009/0215879; Table 3).
Parameter 3
The breadth of the claimed dosages of the claimed nucleic acid constructs to be administered is enormously broad, as the independent claims fail to recite the minimal dosage of the broadly claimed vectors, recited at a high level of generality, that is to be administered to the human patient.
The claimed methods are recited at a high level of generality for the nucleic acid vector dosage that is to be administered, including, but not limited to, as little as 1x10^2 to 1x10^20 vector genomes, or more (e.g. Vetter et al (U.S. 2023/0103708, [0152]).
Parameter 4
The claimed methods are recited at a high level of generality for the multitude of anatomically distinct administration routes, including, but not limited to, delivery and administration systemically, regionally or locally by intravenous injection, infusion, intracranially, intra-spinal, intrathecal, intracerebroventricular, intra-cistemal magna, intrastriatal, or intranigral injection, or injection into any brain region.
Parameter 5
The claims are broad for reasonably encompassing an enormous genus of physiologically and phenotypically different results, which evokes the question: A therapeutically effective amount to do what?
The recitation implies a genus of unrecited and undisclosed phenotypes by which the therapeutically effective dose is to be determined and/or identified, thereby rendering the claim indefinite. A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
The specification discloses, for example:
i) slowing the progression of a synucleinopathy [013], whereby that which is/is not “slowing” is/are considered to be an arbitrary and subjective determination;
ii) alleviation of symptoms, [059], whereby that which is/is not “alleviation” is/are considered to be an arbitrary and subjective determination;
iii) prevention of one or more symptoms [059];
iv) improvement of quality of life [059], whereby that which is/is not “improvement” is/are considered to be an arbitrary and subjective determination; and
v) increased survival [059], whereby that which is/is not “increased survival” is/are considered to be an arbitrary and subjective determination given that there is no objective reference from which to measure said increased survival. There is only one human patient, who is either dead or alive. One cannot measure increased survival on the treated patient because said patient is no longer non-treated, from which to objectively measure “increased survival”.
While the instant specification does disclose an in vivo embodiment of administering to a mouse animal model an AAV6 viral vector encoding a ZFP-TF via bilateral injection into the striatum (e.g. Example 3, [079]), such merely demonstrates the ability to express the ZFP-TF in a brain cell.
While Example 3 discloses an in vivo animal model comprising bilateral injection into the mouse brain of AAV6 vectors encoding the ZFP-TF, the example is silent to the actual dosage administered. The ordinary artisan would not be able to extrapolate a dosage from such obfuscation.
The claims fail to recite, and the specification fails to disclose, a first dosage [parameter 3] of a first nucleic acid construct, e.g. a mRNA molecule [parameter 2], administered via intravenous injection [parameter 4] to the genus of about 1x10^6 species of non-human xenograft animal models [parameter 1] that will necessarily and predictably achieves the ability to cross the blood-brain-barrier to thereby cause expression of the ZFP-TF in a human brain cell within said xenograft animal models, as opposed to a second dosage [parameter 3] of a second nucleic acid construct, e.g. phagemid [parameter 2], administered via intravenous injection [parameter 4] to the genus of about 1x10^6 species of non-human xenograft animal models [parameter 1] that will necessarily and predictably achieves the ability to cross the blood-brain-barrier to thereby cause expression of the ZFP-TF in a human brain cell within said xenograft animal models, for example.
The claims fail to recite, and the specification fails to disclose, a first dosage [parameter 3] of a first nucleic acid construct, e.g. a bacterial artificial chromosome [parameter 2], administered via intravenous injection [parameter 4] to the genus of about 1x10^6 species of non-human xenograft animal models [parameter 1] that will necessarily and predictably achieves the ability to cross the blood-brain-barrier to thereby cause expression of the ZFP-TF in a human brain cell within said xenograft animal models, as opposed to a second dosage [parameter 3] of a second nucleic acid construct, e.g. measles virus [parameter 2], administered via intravenous injection [parameter 4] to the genus of about 1x10^6 species of non-human xenograft animal models [parameter 1] that will necessarily and predictably achieves the ability to cross the blood-brain-barrier to thereby cause expression of the ZFP-TF in a human brain cell within said xenograft animal models, for example.
The claims fail to recite, and the specification fails to disclose, a first dosage [parameter 3] of a first nucleic acid construct, e.g. a mRNA molecule [parameter 2], administered via injection into any region of the brain [parameter 4] to the genus of about 1x10^6 species of non-human xenograft animal models [parameter 1] that will necessarily and predictably achieve expression of the ZFP-TF in a human brain cell within said xenograft animal models, as opposed to a second dosage [parameter 3] of a second nucleic acid construct, e.g. phagemid [parameter 2], administered via injection into any region of the brain [parameter 4] to the genus of about 1x10^6 species of non-human xenograft animal models [parameter 1] that will necessarily and predictably achieves expression of the ZFP-TF in a human brain cell within said xenograft animal models, for example.
The claims fail to recite, and the specification fails to disclose, a first dosage [parameter 3] of a first nucleic acid construct, e.g. a bacterial artificial chromosome [parameter 2], administered via injection into any region of the brain [parameter 4] to the genus of about 1x10^6 species of non-human xenograft animal models [parameter 1] that will necessarily and predictably achieves expression of the ZFP-TF in a human brain cell within said xenograft animal models, as opposed to a second dosage [parameter 3] of a second nucleic acid construct, e.g. measles virus [parameter 2], administered via injection into any region of the brain [parameter 4] to the genus of about 1x10^6 species of non-human xenograft animal models [parameter 1] that will necessarily and predictably achieves expression of the ZFP-TF in a human brain cell within said xenograft animal models, for example.
Rather, the ordinary artisan would recognize that the pharmaceutical composition must be administered directly to the human xenografted brain cells.
The claims fail to recite, and the specification fails to disclose, a first dosage [parameter 3] of a first nucleic acid construct, e.g. a bacterial artificial chromosome [parameter 2], administered via injection into any region of the brain [parameter 4] to the genus of about 1x10^6 species of non-human xenograft animal models [parameter 1] that will necessarily and predictably achieves expression of the ZFP-TF in a human brain cell, more specifically a neuron, but not a neuroepithelial cell (Claim 19), within said xenograft animal models, as opposed to a second dosage [parameter 3] of a second nucleic acid construct, e.g. measles virus [parameter 2], administered via injection into any region of the brain [parameter 4] to the genus of about 1x10^6 species of non-human xenograft animal models [parameter 1] that will necessarily and predictably achieves expression of the ZFP-TF in a human brain cell, more specifically a glial cell, but not an ependymal cell (Claim 19), within said xenograft animal models, for example.
The claims fail to recite, and the specification fails to disclose, a first dosage [parameter 3] of a first nucleic acid construct, e.g. a mRNA molecule [parameter 2], administered via injection into any region of the brain [parameter 4] to the genus of about 1x10^6 species of non-human xenograft animal models [parameter 1] that will necessarily and predictably achieve expression of the ZFP-TF in a human brain cell, more specifically a neuroepithelial cell, but not an ependymal cell (Claim 19), within said xenograft animal models, as opposed to a second dosage [parameter 3] of a second nucleic acid construct, e.g. phagemid [parameter 2], administered via injection into any region of the brain [parameter 4] to the genus of about 1x10^6 species of non-human xenograft animal models [parameter 1] that will necessarily and predictably achieves expression of the ZFP-TF in a human brain cell, more specifically a glial cell, but not a neuron (Claim 19), within said xenograft animal models, for example.
The instant specification fails to disclose a working example whereby intravenous administration [parameter 4] of the enormously broad genus of double-stranded DNA, RNA, plasmids, cosmids, transposons, phages, and viral vector [parameter 2] at an enormously broad genus of structurally undisclosed dosages, respectively [parameter 3] necessarily and predictably achieves a real-world, and clinically meaningful treatment of a synucleinopathy in a human subject, whereby the therapeutic result includes, but is not limited to:
i) slowing the progression of a synucleinopathy, whereby that which is/is not “slowing” is/are considered to be an arbitrary and subjective determination;
ii) alleviation of symptoms, whereby that which is/is not “alleviation” is/are considered to be an arbitrary and subjective determination;
iii) prevention of one or more symptoms;
iv) improvement of quality of life, whereby that which is/is not “improvement” is/are considered to be an arbitrary and subjective determination; and
v) increased survival, whereby that which is/is not “increased survival” is/are considered to be an arbitrary and subjective determination given that there is no objective reference from which to measure said increased survival [parameter 5].
The claims fail to recite, and the specification fails to disclose, a first dosage [parameter 3] of a first nucleic acid construct, e.g. a mRNA molecule [parameter 2], administered via intravenous injection [parameter 4] that will necessarily and predictably achieves the ability to cross the blood-brain-barrier to thereby cause expression of the ZFP-TF in a human brain cell, let alone necessarily and predictably achieves a real-world, and clinically meaningful treatment of a synucleinopathy in a human subject, whereby the therapeutic result includes, but is not limited to “increased survival” [parameter 5], as opposed to a second dosage [parameter 3] of a second nucleic acid construct, e.g. phagemid [parameter 2], administered via intravenous injection [parameter 4] that will necessarily and predictably achieves the ability to cross the blood-brain-barrier to thereby cause expression of the ZFP-TF in a human brain cell, let alone necessarily and predictably achieves a real-world, and clinically meaningful treatment of a synucleinopathy in a human subject, whereby the therapeutic result includes, but is not limited to prevention of one or more symptoms [parameter 5], for example.
The claims fail to recite, and the specification fails to disclose, a first dosage [parameter 3] of a first nucleic acid construct, e.g. a bacterial artificial chromosome [parameter 2], administered via intravenous injection [parameter 4] that will necessarily and predictably achieves the ability to cross the blood-brain-barrier to thereby cause expression of the ZFP-TF in a human brain cell, let alone necessarily and predictably achieves a real-world, and clinically meaningful treatment of a synucleinopathy in a human subject, whereby the therapeutic result includes, but is not limited to slowing the progression of a synucleinopathy [parameter 5], as opposed to a second dosage [parameter 3] of a second nucleic acid construct, e.g. measles virus [parameter 2], administered via intravenous injection [parameter 4] that will necessarily and predictably achieves the ability to cross the blood-brain-barrier to thereby cause expression of the ZFP-TF in a human brain cell, let alone necessarily and predictably achieves a real-world, and clinically meaningful treatment of a synucleinopathy in a human subject, whereby the therapeutic result includes, but is not limited to alleviating of one or more symptoms [parameter 5], for example.
Pruett et al (Comparison of Zinc Finger Nucleases for Use in Gene Targeting in Mammalian Cells, Molecular Therapy 16(4): 707-717, 2008; of record) is considered relevant prior art for having taught that although conceptually ZFPs can be made to recognize new target sequences by mixing and matching individual fingers with known recognition sites (syn. modular assembly), this approach has limitations because it does not take into account the potential interactions between fingers in DNA-binding interactions, which are important in determining target sequence affinity and specificity (e.g. pgs 707-708, joining para). One study reporting that ZFNs made by modular-assembly had only a 50% success rate, and they were never able to target a natural site. Clearly, there are deficiencies in the published methods of making ZFNs for targeting mammalian cells. (pg 708, col. 1).
Gupta et al (Zinc finger protein-dependent and -independent contributions to the in vivo off-target activity of zinc finger nucleases, Nucleic Acids Research 39(1): 381-392, 2011; of record) is considered relevant prior art for having taught that many ZFPs display dose-dependent toxicity due to undesired off-target effects (e.g. Abstract). For each ZFP, the number of binding sites within a genome is primarily dictated by the number and quality of the incorporated zinc fingers (e.g. pg 382, col. 1).
Instant claims recite the ZFPs at a high level of generality, with varying numbers of zing fingers, and no required minimal degree of specificity and/or binding affinity.
Gupta et al also taught that the number of functional target sites is also defined by the composition and length of the linker joining the ZFP and nuclease domain, which determines the required spacing between ZFP half-sites for activity (e.g. pg 382, col. 1).
Moreira et al (Hot spots—A review of the protein–protein interface determinant amino-acid residues, Proteins 68: 803-812, 2007; of record) is considered relevant prior art for having taught that protein–protein interactions are very complex and can be characterized by their size,
shape, and surface complementarity (e.g. pg 803, Protein-Protein). The hydrophobic and electrostatic interactions they establish, as well as the flexibility of the molecules involved, are very significant.
Moreira et al taught that in a protein–protein interface, a small subset of the buried amino acids typically contribute to the majority of binding affinity as determined by the change in the free energy of binding. Although there is no purely geometric reason, these energetic determinants are compact, centralized regions of residues crucial for protein association (e.g. pg 804, col. 2).
Moreira et al taught that most interfaces are optimal tight-fitting regions characterized by complementary pockets scattered through the central region of the interface, and enriched in structurally conserved residues. These pockets are classified as ‘‘complementary’’ because there is a large complementarity both in shape and in the juxtaposition of hydrophobic and hydrophilic hot spots, with buried charged residues forming salt bridges and hydrophobic residues from one surface fitting into small nooks on the opposite face. Usually, the hot spot of one face packs against the hot spot of the other face establishing a region determinant for complex binding (e.g. pg 806, col. 1). Complementarity is basically affected by the size of the buried surface, alignment of polar and nonpolar residues, number of buried waters, and the packing densities of atoms involved in the protein–protein interface. Packing defects at the protein–protein interface result in these gaps or pockets, and it is unclear whether unfilled pockets contain water molecules or how the dynamics of water molecules entering and escaping these pockets may affect binding stability (e.g. pg 807, col. 2). Moreira et al taught that common methodology to determine hot spot locations on the artisan’s protein of interest, alanine-scanning mutagenesis is slow and labor-intensive (e.g. pg 804, col. 1). Similarly, systematic mutagenesis is very laborious and time-consuming to perform, as individual mutant proteins must be purified and analyzed separately (e.g. pg 808, col. 2).
Ng et al (Predicting the Effects of Amino Acid Substitutions on Protein Function, Annual Review Genomics Human Genetics 7: 61-80, 2006; of record) is considered relevant prior art for having taught that non-synonymous nucleotide changes which introduce amino acid changes in the corresponding protein have the largest impact on human health. Most algorithms to predict amino acid substation consequences of protein function indicate about 25% to 30% of amino acid changes negatively affect protein function (Abstract). Existing prediction tools primarily focus on studying the deleterious effects of single amino acid substitutions through examining amino acid conservation at the position of interest among related sequences, an approach that is not directly applicable to multiple amino acid changes, including insertions or deletions. Ng et al taught that 83% of disease-causing mutations affect protein stability (e.g. pg 63, col. 1), which in this case, would affect the ability of the ZFP protein variants to necessarily and predictably have the functional properties of recognizing one or more structurally undisclosed nucleic acid target sequences in a human SNCA gene, let alone within 1000 and/or 500 nucleotides of the SNCA transcription start stie 1, 2a, and/or 2b.
Ng et al taught that while multiple sequence alignment of the homologous sequences reveals what positions have been conserved throughout evolutionary time, and these positions are inferred to be important for function (e.g. pg 63, col. 1), Users should be cautious even with proteins that are judged to be orthologous based on phylogeny. Orthologous genes in different species are derived from a common ancestor, but they may not necessarily have the same function. If function has changed, then amino acids that are important for the function of one protein may not necessarily be important for the function of the ortholog. 2% of disease-causing mutations in human genes are identical to the sequences of their respective mouse orthologs, suggesting that even though these positions have huge phenotypic effects on human health, they have different roles or are no longer important in mice If the orthologs in alignment have slightly different functions, then the positions that differentiate function among orthologs may be incorrectly predicted. (e.g. pg 68, col. 1). When there are many missense mutations in the gene(s) of interest, assaying all missense mutations, which introduce amino acid changes, can be expensive and time-consuming (e.g. pg 74, col. 1). Prediction accuracy has gradually improved, but few head-to-head comparisons exist. Moreover, as the number of servers providing AAS prediction increases, it will become increasingly difficult for investigators to interpret the predictions. (e.g. pg 74, col. 2). Ng et al taught that the error rate of functional annotations in the sequence database is considerable, making it even more difficult to infer correct function from a structural comparison of a new sequence with a sequence database (e.g. Table 1, error rates of about 40% to 60%).
Prediction of protein structure by homology and/or algorithm is notoriously difficult, as one of ordinary skill in the art would immediately understand.
Disclosure of putative structures having a theorized function in the absence of experimental data demonstrating the theorized function is insufficient to demonstrate possession of a representative number of species by disclosure of relevant, identifying characteristics (i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics), sufficient to show the applicant was in possession of the claimed invention.
Considering the mode of administration, the specification simply requires administration of the nucleic acid construct to the subject by any means. The art has demonstrated through numerous publications, delivery of nucleic acid vectors in vivo is highly unpredictable for successful human therapy.
At issue in general are organ barriers, failure to persist, side-effects in other organs, T-cell responses, virus neutralizing antibodies, humoral immunity, normal tropism of the vector to other organs and more. The challenge is to maintain the efficiency of delivery and expression while minimizing any pathogenicity of the virus from which the vector was derived. The inability to develop an adequate means of overcoming obstacles such as humoral; responses and refractory cells limits the successful means by which the nucleic acid can be administered. The physiological art is recognized as unpredictable. (MPEP 2164.03.) In cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws. In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved. In this case, the nucleic acid is broadly stated as being administered to a patient. The lack of guidance exacerbates the highly unpredictable field of gene therapy and the method of delivery of polynucleotides is highly unpredictable to date. Gene delivery has been a persistent problem for gene therapy protocols and the route of delivery itself presents an obstacle to be overcome for the application of the vector therapeutically.
Fumoto et al (Targeted Gene Delivery: Importance of Administration Routes, INTECH, Novel Gene Therapy Approaches, pg 3-31; editors Wei and Good, publisher Books on Demand, 2013; of record) details these obstacles wherein direct injection is to date the best procedure (pg 11, Table 3, Figure 3, “Direct injection of rAAV vector…exhibited faster and stronger transgene expression than intravenous and intraportal injections”).
To date, no single mode of gene transfer has provided a viable option for successful gene therapy protocols (Daya et al, Gene Therapy Using Adeno-Associated Virus Vectors, Clin. Microbiol. Rev. 21(4): 583-593, 2008; pg 590-591, joining ¶; of record). When considering AAV therapy, there are many obstacles to its use systemically- host cell immune response which leads to toxicity (Daya et al, pg 587, col 2), blood brain as well as cellular barriers against the virus, adequate expression, degradation of the vector or the product. Even the use of targeting methods and tissue specific promoters have done little to overcome the numerous obstacles related to gene delivery. Even use of tissue specific promoters and capsids targeting has not successfully overcome these obstacles. Taken together with the large breadth of target tissues and diseases claimed, in light of the difficulties to overcome even one of these barriers, one could not perform the full breadth of the claims.
Huang et al (Genetic Manipulation of Brown Fat Via Oral Administration of an Engineered Recombinant Adeno-associated Viral Serotype Vector, Molecular Therapy 24(6): 1062-1069, 2016; of record) is considered relevant prior art for having taught oral administration of rAAV, whereupon transgene expression was not detected in heart, stomach, intestine, skeletal muscle, kidney, spleen, lung, nor brain (e.g. pg 1062, col. 2; Figure 2).
Tian et al (Aerosol Inhalation-mediated Delivery of an Adeno-associated Virus 5-expressed Antagonistic Interleukin-4 Mutant Ameliorates Experimental Murine Asthma, Archives of Medical Research 50: 384-392, 2019; of record) is considered relevant art for having taught inhaled administration of rAAV, whereupon AAV vector DNA was detected in the lung, but not detected in other organs, such as heart, liver, kidney, brain, lymph nodes, and gonads (e.g. Abstract; pg 386, col. 2).
Ghoraba et al (Ocular Gene Therapy: A Literature Review with Special Focus on Immune and Inflammatory Responses, Clinical Opthalmology 16: 1753-1771, 2022; of record) is considered relevant post-filing art for having taught that the associated immune and inflammatory reactions to gene therapy, including rAAV-based gene therapies, may render such treatment ineffective or harmful, which are of particular concerns for the eyes due to their susceptibility to inflammation. The route of administration directly impacts the degree of immune and inflammatory reaction. Several instances of vision loss due to severe late onset intraocular inflammation were reported in a clinical trial involving intravitreal delivery of viral vectors (Abstract). Intravitreal administration, while convenient, is unable to transduce the outer retina layers, which is the main target of most retinal diseases due to defects in the RPE or photoreceptor cells (e.g. pg 1762, Intravitreal Delivery). Studies on humans and NHPs have demonstrated consistently that intravitreal delivery of vectors induces a significant humoral immune response. The response is marked by the production of Abs, which may not lead to inflammation, but can significantly reduce the efficacy of treatment by attacking and eliminating transduced cells through the neutralizing antibodies (pg 1763, para 1).
Acland et al (U.S. 2004/0022766; of record) is considered relevant prior art for having disclosed a recombinant adeno-associated virus (rAAV), said rAAV comprising an AAV capsid [0023], and a vector genome packaged therein, said vector genome comprising:
(a) an AAV 5' inverted terminal repeat (ITR) sequence;
(b) a promoter;
(c) a coding sequence encoding a human Lebercilin [0031].
Acland et al disclosed [0057] “[T]he use of subretinal injection as the route of delivery is a critical component of this method, as intravitreal administration does not enable the same therapeutic effects. The vector and carrier cannot diffuse across the multiple cell layers in the retina to reach the RPE, when intravitreal injection is used. Similarly, intravenous delivery is unacceptable because the material does not penetrate the blood-brain (blood-retina) barrier. Because the virus does not diffuse well, topical administration is similarly not preferred for this method.”
Reliance on animal models is not predictive of clinical outcome. This has been complicated by the inability to extrapolate delivery methods in animals with those in humans or higher animals.
Mingozzi and High (Immune responses to AAV vectors: overcoming barriers to successful gene therapy, Blood 122(1): 23-36, 2013; of record) demonstrate that the human findings are not recapitulated from the animal studies (page 26, col 2, “it seemed logical that one could model the human immune response in these animals, but multiple attempts to do so have also failed”). Hence, lessons learned from small animals such as the mice studies could not recapitulate the ability to deliver adequately in humans.
Kattenhorn et al (Adeno-Associated Virus Gene Therapy for Liver Disease, Human Gene Therapy 27(12): 947-961, November 28, 2016; of record) taught concerns for translation lead to extensive analysis of the effects on clinical use. The use of AAV after initial promising results went on hiatus (pg 947, col. 2, “clinical hiatus in the field”) as the animal models were deficient (pg 953, col. 2, “Although animal models predicted many aspects of the human immune response…, they largely failed to predict responses to AAV capsid”; “Work done in nonhuman primates has not met with any additional success”). This emphasizes that the challenge in humans is to maintain the efficiency of delivery and expression while minimizing any pathogenicity of the virus from which the vector was derived. Eventually, the use of AAV is serotype-dependent (e.g. pg 950, col. 1), organ and concentration dependent. The inability to develop an adequate means of overcoming humoral responses, neutralizing antibody, inactivation of transgene expression, shedding and refractory cells limits the successful means by which the nucleic acid can be administered.
Ferdowsian et al (Primates in Medical Research: A Matter of Convenience, not Sound Science, The Hastings Center, www.thehastingscenter.org/primates-in-medical-research-convenience-not-sound-science/; July 8, 2022; last visited September 27, 2024; of record) is considered relevant art for having taught that, “Today, unlike in the 17th century, scientists easily recognize the truth in the saying “mice lie and monkeys exaggerate,” which points to a well-known problem in biomedical research: using nonhuman primates and other animals in research fails more often than it succeeds.”
It is generally recognized in the art that biological compounds often react unpredictably under different circumstances (Nationwide Chem. Corp. v. Wright, 458 F. supp. 828, 839, 192 USPQ95, 105(M.D. Fla. 1976); Affd 584 F.2d 714, 200 USPQ257 (5th Cir. 1978); In re Fischer, 427 F.2d 833, 839, 166 USPQ 10, 24(CCPA 1970)). The relative skill of the artisan and the unpredictability of the pharmaceutical art are very high. Where the physiological activity of a chemical or biological compound is considered to be an unpredictable art (Note that in cases involving physiological activity such as the instant case, "the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved" (See In re Fischer, 427 F.2d 833, 839, 166 USPQ 10, 24(CCPA 1970))), the skilled artisan would have not known how to administer to a human subject or the genus of about 1x10^6 non-human xenograft animal species [parameter 1] via intravenous injection or anywhere in the brain [parameter 4] a first dosage recited at a high level of generality [parameter 3] of a first nucleic acid pharmaceutical recited at a high level of generality [parameter 2] encoding the ZFP-TF protein variants that will necessarily and predictably achieves expression of the ZFP-TF in a human brain cell (Claim 18), let alone necessarily and predictably achieves a real-world and clinically meaningful therapeutic result (Claim 23), including, but not limited to:
i) slowing the progression of a synucleinopathy, whereby that which is/is not “slowing” is/are considered to be an arbitrary and subjective determination;
ii) alleviation of symptoms, whereby that which is/is not “alleviation” is/are considered to be an arbitrary and subjective determination;
iii) prevention of one or more symptoms;
iv) improvement of quality of life, whereby that which is/is not “improvement” is/are considered to be an arbitrary and subjective determination; and/or
v) increased survival, whereby that which is/is not “increased survival” is/are considered to be an arbitrary and subjective determination given that there is no objective reference from which to measure said increased survival [parameter 5] in a human patient, including human patients suffering from Parkinson’s disease, Lewy body dementia, Alzheimer’s disease, or multiple system atrophy (Claim 25).
The instant portion of the invention, as claimed, falls under the "germ of an idea" concept defined by the CAFC. The court has stated that "patent protection is granted in return for an enabling disclosure, not for vague intimations of general ideas that may or may not be workable". The court continues to say that "tossing out the mere germ of an idea does not constitute an enabling disclosure" and that "the specification, not knowledge in the art, that must supply the novel aspects of an invention in order to constitute adequate enablement". (See Genentech Inc v. Novo Nordisk A/S 42 USPQ2d 1001, at 1005). The claimed methods constitute such a "germ of an idea".
The courts have stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in patent application. 27 USPQ2d 1662 Exparte Maizel. In the instant case, in view of the lack of guidance, working examples, breadth of the claims, the level of skill in the art and state of the art at the time of the claimed invention was made, it would have required undue experimentation to make and/or use the invention as claimed.
If little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. See, e.g., Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004) ("Nascent technology, however, must be enabled with a 'specific and useful teaching.' The law requires an enabling disclosure for nascent technology because a person of ordinary skill in the art has little or no knowledge independent from the patentee's instruction. Thus, the public's end of the bargain struck by the patent system is a full enabling disclosure of the claimed technology." (citations omitted)).
As In re Gardner, Roe and Willey, 427 F.2d 786,789 (C.C.P.A. 1970), the skilled artisan might eventually find out how to use the invention after “a great deal of work”. In the case of In re Gardner, Roe and Willey, the invention was a compound which the inventor claimed to have antidepressant activity, but was not enabled because the inventor failed to disclose how to use the invention based on insufficient disclosure of effective drug dosage. The court held that “the law requires that the disclosure in the application shall inform them how to use, not how to find out how to use for themselves”.
Perrin (Make mouse studies work, Nature (507): 423-425, 2014; of record) taught that the series of clinical trials for a potential therapy can cost hundreds of millions of dollars. The human costs are even greater (pg 423, col. 1). For example, while 12 clinical trials were tested for the treatment of ALS, all but one failed in the clinic (pg 423, col. 2). Experiments necessary in preclinical animal models to characterize new drugs or therapeutic compounds are expensive, time-consuming, and will not, in themselves, lead to new treatments. But without this upfront investment, financial resources for clinical trials are being wasted and [human] lives are being lost (pg 424, col. 1). Animal models are highly variable, and require a large number of animals per test group. Before assessing a drug’s efficacy, researchers should investigate what dose animals can tolerate, whether the drug reaches the relevant tissue at the required dose and how quickly the drug is metabolized or degraded by the body. We estimate that it takes about $30,000 and 6–9 months to characterize the toxicity of a molecule and assess whether enough reaches the relevant tissue and has a sufficient half-life at the target to be potentially effective. If those results are promising, then experiments to test whether a drug can extend an animal’s survival are warranted — this will cost about $100,000 per dose and take around 12 months. At least three doses of the molecule should be tested; this will help to establish that any drug responses are real and suggest what a reasonable dosing level might be. Thus, even assuming the model has been adequately characterized, an investment of $330,000 is necessary just to determine whether a single drug has reasonable potential to treat disease in humans. It could take thousands of patients, several years and hundreds of millions of dollars to move a drug through the clinical development process. The investment required in time and funds is far beyond what any one lab should be expected to do. (pg 425, col.s 2-3). The human costs are even greater: patients with progressive terminal illnesses may have just one shot at an unproven but promising treatment. Clinical trials typically require patients to commit to year or more of treatment, during which they are precluded from pursuing other experimental options (pg 423, col.2 1-3).
Greenberg (Gene Therapy for heart failure, Trends in Cardiovascular Medicine 27: 216-222, 2017; of record) is considered relevant prior art for taught that despite success in experimental animal models, translating gene transfer strategies from the laboratory to the clinic remains at an early stage (Abstract). The success of gene therapy depends on a variety of factors that will ultimately determine the level of transgene expression within the targeted cells. These factors include the vector used for delivery, the method and conditions of delivery of the vector to the [target tissue], the dose that is given and interactions between the host and the vector that alter the efficiency of transfection of [target] cells (e.g. pg 217, col. 1). Failure of therapeutic results may arise because the vector DNA levels were at the lower end of the threshold for dose-response curves in pharmacology studies, and/or only a small proportion of target cells were expressing the therapeutic transgene (e.g. pg 220, col. 1). Although the use of AAVs for gene therapy is appealing, additional information about the best strain of AAVs to use in human patients is needed. Experience indicates that there is a need to carefully consider the dose of the gene therapy vector; however, this has proved to be difficult in early phase developmental studies due to the complexity and cost of such studies (e.g. pg 221, col. 1).
Maguire et al (Viral vectors for gene delivery to the inner ear, Hearing Research 394: e107927, 13 pages, doi.org/10.1016/j.heares.2020.107927, 2020; of record) is considered relevant post-filing art for taught that despite the progress with AAV vectors in the inner ear, little is known regarding the mechanism of transduction of specific cells by AAV within the cochlea (e.g. pg 2, col. 2). There are limitations to what experiments in mice can tell us about the true translation potential of a new therapeutic (e.g. pg 8, col. 2), e.g. species-related physiological differences between mice and humans (e.g. pg 9, col. 1). The AAV dosage is a significant factor in achieving transduction of the target cell, as insufficient dosage may achieve no transduction of the target cells (e.g. pg 9, col. 2).
Tobias (Mouse Study Used in Research, Multiple Sclerosis News Today, multiplesclerosisnewstoday.com/news-posts/2023/09/08/lets-not-get-overexcited-about-any-mice-study-used-research/; September 8, 2023; last visited September 27, 2024) s considered relevant art for having taught that, “Mice exaggerate and monkeys lie, some researchers jokingly say. (Or is it the other way around?)” The odds of an experimental treatment making it from mouse or monkey to human are very low. Less than 8% of cancer treatments make it from animal studies into a clinical setting, where they’re tested on people, and only 10% of the medications in those clinical trials make it through to government approval. No wonder some researchers joke about mice and monkeys lying and exaggerating.
The specification fails to make up for the deficiencies of the global scientific community.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”).
Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)
The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 “merely by clearly describing one embodiment of the thing claimed.” LizardTech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1346, 76 USPQ2d 1731, 1733 (Fed. Cir. 2005).
For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are “representative of the full variety or scope of the genus,” or by the establishment of “a reasonable structure-function correlation.” Such correlations may be established “by the inventor as described in the specification,” or they may be “known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014)
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function ... does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is’).
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, knowing that the initial nucleic acid construct encodes a fusion protein comprising a transcription repressor domain and a ZFP domain of Claim 9 does not tell you anything at about how to administer to a human subject or the genus of about 1x10^6 non-human xenograft animal species [parameter 1] via intravenous injection or anywhere in the brain [parameter 4] a first dosage recited at a high level of generality [parameter 3] of a first nucleic acid pharmaceutical recited at a high level of generality [parameter 2] encoding the ZFP-TF protein variants that will necessarily and predictably achieves expression of the ZFP-TF in a human brain cell (Claim 18), let alone necessarily and predictably achieves a real-world and clinically meaningful therapeutic result (Claim 23), including, but not limited to:
i) slowing the progression of a synucleinopathy, whereby that which is/is not “slowing” is/are considered to be an arbitrary and subjective determination;
ii) alleviation of symptoms, whereby that which is/is not “alleviation” is/are considered to be an arbitrary and subjective determination;
iii) prevention of one or more symptoms;
iv) improvement of quality of life, whereby that which is/is not “improvement” is/are considered to be an arbitrary and subjective determination; and/or
v) increased survival, whereby that which is/is not “increased survival” is/are considered to be an arbitrary and subjective determination given that there is no objective reference from which to measure said increased survival [parameter 5] in a human patient, including human patients suffering from Parkinson’s disease, Lewy body dementia, Alzheimer’s disease, or multiple system atrophy (Claim 25).
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that the claimed class of the ZFP-TF fusion proteins reasonably encompass an enormously vast genus of unrecited and undisclosed nucleic acid pharmaceutical formularies [parameter 2], and their corresponding respective dosages [parameter 3] to be administered [parameter 4] to the genus of about 1x10^6 human and non-human animal subjects [parameter 1] that will necessarily and predictably achieve expression of the ZFP-TF fusion proteins in a human brain cell, thereby inhibiting expression of alpha-synuclein in the human brain cell (Claim 18), let alone, achieve a real-world and clinically-meaningful treatment [parameter 5] of human patients suffering from a synucleinopathy (Claim 23), including Parkinson’s disease, Lewy body dementia, Alzheimer’s disease, or multiple system atrophy (Claim 25).
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
Applicant’s working examples are directed to the mouse model system, wherein the mice were administered by direct bilateral injection into the brain a pharmaceutical composition comprising rAAV virus particles whose genomes encoded the specific ZFP-TF 92195 or ZFP-TF 82264, each of which is disclosed to have minimal to no detectable off-target activity in human and mouse neurons, and capable of repressing SNCA gene expression by about 80% (ZFP-TF 82264) or about 95% (ZFP-TF 82195).
However, as discussed above Example 3 is silent to the actual dosage administered. The ordinary artisan would not be able to extrapolate a dosage from such obfuscation.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
Response to Arguments
Applicant argues that Claim 9 has been amended to recite a ZFP domain comprising, in F1 to F6 order, the DNA-binding recognition helix sequences SEQ ID NO:43-68-83-103-44-125, and thus the ordinary artisan would recognize Applicant’s possession of the claimed subject matter.
Applicant’s argument(s) has been fully considered, but is not persuasive. Applicant’s argument is not on point. While it is clear that Claim 9 is in condition for Allowance, Claim 9 does nothing to address the substantive issues for the, at least, first, second, third, fourth, and fifth method step parameters discussed above in order to necessarily and predictably achieve the claimed preambles of said methods.
14. Claims 18-23, 25, and 49 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement.
The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The Examiner incorporates herein the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description rejection.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
Response to Arguments
Applicant argues that there is no undue experimentation to perform the claimed methods.
Applicant’s argument(s) has been fully considered, but is not persuasive.
knowing that the initial nucleic acid construct encodes a fusion protein comprising a transcription repressor domain and a ZFP domain of Claim 9 does not tell you anything at about how to administer to a human subject or the genus of about 1x10^6 non-human xenograft animal species [parameter 1] via intravenous injection or anywhere in the brain [parameter 4] a first dosage recited at a high level of generality [parameter 3] of a first nucleic acid pharmaceutical recited at a high level of generality [parameter 2] encoding the ZFP-TF protein variants that will necessarily and predictably achieves expression of the ZFP-TF in a human brain cell (Claim 18), let alone necessarily and predictably achieves a real-world and clinically meaningful therapeutic result (Claim 23), including, but not limited to:
i) slowing the progression of a synucleinopathy, whereby that which is/is not “slowing” is/are considered to be an arbitrary and subjective determination;
ii) alleviation of symptoms, whereby that which is/is not “alleviation” is/are considered to be an arbitrary and subjective determination;
iii) prevention of one or more symptoms;
iv) improvement of quality of life, whereby that which is/is not “improvement” is/are considered to be an arbitrary and subjective determination; and/or
v) increased survival, whereby that which is/is not “increased survival” is/are considered to be an arbitrary and subjective determination given that there is no objective reference from which to measure said increased survival [parameter 5] in a human patient, including human patients suffering from Parkinson’s disease, Lewy body dementia, Alzheimer’s disease, or multiple system atrophy (Claim 25).
While Example 3 discloses an in vivo animal model comprising bilateral injection into the mouse brain of AAV6 vectors encoding the ZFP-TF, the example is silent to the actual dosage administered. The ordinary artisan would not be able to extrapolate a dosage from such obfuscation.
Those of ordinary skill in the art would immediately recognize that independent Claims 18 and 23 are far broader in scope than Applicant’s Example 3.
As discussed above, those of ordinary skill in the art have long-recognized that reliance on animal models is not predictive of clinical outcome. This has been complicated by the inability to extrapolate delivery methods in animals with those in humans or higher animals.
While it seems logical that one could model the human immune response in animals, multiple attempts to do so have failed. Hence, lessons learned from small animals such as the mice studies could not recapitulate the ability to deliver adequately in humans (Mingozzi et al).
The use of AAV after initial promising results went on hiatus as the animal models were deficient, as they largely failed to predict responses to AAV capsid, and work done in nonhuman primates has not met with any additional success. This emphasizes that the challenge in humans is to maintain the efficiency of delivery and expression while minimizing any pathogenicity of the virus from which the vector was derived. Eventually, the use of AAV is serotype-dependent, organ and concentration dependent. The inability to develop an adequate means of overcoming humoral responses, neutralizing antibody, inactivation of transgene expression, shedding and refractory cells limits the successful means by which the nucleic acid can be administered (Kattenhorn et al).
No wonder some researchers joke about mice and monkeys lying and exaggerating (Ferdowsian et al; Tobias).
The investment required in time and funds is far beyond what any one lab should be expected to do. The human costs are even greater: patients with progressive terminal illnesses may have just one shot at an unproven but promising treatment (Perrin).
Despite success in experimental animal models, translating gene transfer strategies from the laboratory to the clinic remains at an early stage. The success of gene therapy depends on a variety of factors that will ultimately determine the level of transgene expression within the targeted cells. These factors include the vector used for delivery, the method and conditions of delivery of the vector to the [target tissue], the dose that is given and interactions between the host and the vector that alter the efficiency of transfection of [target] cells. Failure of therapeutic results may arise because the vector DNA levels were at the lower end of the threshold for dose-response curves in pharmacology studies, and/or only a small proportion of target cells were expressing the therapeutic transgene. Although the use of AAVs for gene therapy is appealing, additional information about the best strain of AAVs to use in human patients is needed. Experience indicates that there is a need to carefully consider the dose of the gene therapy vector; however, this has proved to be difficult in early phase developmental studies due to the complexity and cost of such studies (Greenberg).
There are limitations to what experiments in mice can tell us about the true translation potential of a new therapeutic, e.g. species-related physiological differences between mice and humans. The AAV dosage is a significant factor in achieving transduction of the target cell, as insufficient dosage may achieve no transduction of the target cells (Maguire et al).
The specification fails to make up for the deficiencies of the global scientific community.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
Citation of Relevant Prior Art
15. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Tan et al (U.S. 2009/0215878) is considered relevant prior art for having disclosed zinc finger fusion proteins to be expressed in the dorsal root ganglia of a mammalian subject.
Conclusion
16. Claims 9, 11, 14, 32, 34-38, 41, and 45 are in condition for allowance.
Claims 15-23, 25, 28, 31, 33, 39-40, 42-44, and 46-49 are rejected.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
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