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 .
DETAILED ACTION
Election/Restrictions
Applicant's election with traverse of SEQ ID Nos. 36 and 37 in the reply filed on 06/29/2026 is acknowledged. The traversal is on the ground(s) that the first sequence is a protein and the second sequence is a nucleic acid encoding the protein. This traversal is persuasive and the restriction requirement for a species is withdrawn. SEQ ID Nos. 36-39 will be examined.
Status of the Application
Claims 1-41 are pending and are currently under examination.
Claim Rejections - 35 USC § 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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.
Written Description
Claims 1-41 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by him. The courts have stated:
To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gostelli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious" and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966; Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial Structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed structure, and v. Correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art.
Moreover, the written description requirement for a genus may be satisfied through sufficient description 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 functional and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed 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.
The claims are drawn to a genus of Cas proteins fused with one or more transcriptional activation domains, chimeric Cas proteins, chimeric adapter proteins and gRNA in a CRISPR system for screening genetic vulnerabilities associated with tau aggregation in cells.
When determining 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. In the instant case, the specification describes genome wide screening to identify genetic vulnerabilities associated with tau aggregation using a CRISPR hSAM Cas9 and sgRNA. The prior art of Koonin et al. ("Diversity, classification and evolution of CRISPR-Cas systems." Current opinion in microbiology 37 (2017): 67-78) teach there are numerous different Cas proteins from numerous different organisms (see Figure 1). Koonin et al. illustrates each having different structures based on the different class systems (see Figure 1 and Figure 3). Koonin et al. do not describe these different Cas proteins as having a RuvC active site and an amino acid terminus as claimed.
It is then determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics (i.e. other than nucleotide sequence), specific features and functional attributes that would distinguish different members of the claimed genera. In the instant case, the only other identifying characteristics are identification of certain depletion gene profiles. This functional characteristic does not provide adequate written description for the vast number of different Cas proteins fused with one or more transcriptional activation domains, chimeric Cas proteins, chimeric adapter proteins and gRNA.
A review of the specification shows that it provides no description or guidance that would allow one of skill to distinguish the functional species of the recited structural genus from the non-functional members without empirical determination given, for example, the diversity in different Cas proteins targeted by a gRNA which requires customization to a specific targeting sequence.
Since the disclosure and the prior art fail to describe the common attributes and characteristics concisely identifying members of the proposed genus, and because the claimed genus is highly variant a vast number of different inhibitory oligonucleotides, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus claimed.
"A sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus" (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69) (emphasis added).
Further, “Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.” Ex parte Kubin, 83 USPQ2d 1410, 1417 (Bd. Pat. App. & Int. 2007) citing University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
The MPEP further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is “not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.” MPEP 2163. The MPEP does state that for generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP 2163. Although the MPEP does not define what constitute a sufficient number of representative, the Courts have indicated what do not constitute a representative number species to adequately describe a broad generic. In Gosteli, the Court determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gosteli, 872 F.2d at 1012, 10 USPQ2d at 1618.
Thus the specification and claims lack written description because it is clear that Applicant did not have possession of every Cas proteins fused with one or more transcriptional activation domains, chimeric Cas proteins, chimeric adapter proteins and gRNA used in a screening assay to identify genetic vulnerabilities associated with Tau aggregation.
The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521,222 USPQ 369,372-372 (Fed. Cir. 1984) (affirming rejection because the specification does "little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to one skilled in the relevant art that the inventors, at the time the application was filed, had possession of the entire scope of the claimed invention.
Enablement
Claims 1-41 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification,
while being enabling for methods of screening for genetic vulnerabilities associated with tau aggregation using a CRISPR Streptococcus pyogenes Cas9 assay using Tau biosensor cells in HEK293T stably expressing Tau four-repeat domain,
does not reasonably provide enablement for methods using any chimeric Cas protein fused to one or more transcriptional activation domains, a chimeric adaptor protein fused to any of one or more transcriptional activation domains in any cell type, using any Tau repeat domain in any species and a vast genus of guide RNAs.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The following factors have been considered in the analysis of enablement: (1) the breadth of the claims, (2) the nature of the invention, (3) the state of the prior art, (4) the level of one of ordinary skill, (5) the level of predictability in the art, (6) the amount of direction provided by the inventor, (7) the existence of working examples, (8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The breadth of the claims and the nature of the invention:
The broadest reasonable interpretation of the invention is a method of screening for genetic vulnerabilities associated with tau aggregation using a CRISPR system using any chimeric Cas protein fused to one or more transcriptional activation domains, a chimeric adaptor protein fused to any of one or more transcriptional activation, any cell, any Tau repeat domain and a vast genus of guide RNAs.
Whether the specification would have been enabling as of the filing date involves consideration of the nature of the invention, the state of the prior art, and the level of skill in the art. The state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains. The relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed. See MPEP § 2164.05(b). The state of the prior art provides evidence for the degree of predictability in the art and is related to the amount of direction or guidance needed in the specification as filed to meet the enablement requirement. The state of the prior art is also related to the need for working examples in the specification.
The state of the prior art:
A thorough review of the patent and non-patent literature indicates that the state of the art demonstrating screening for genetic vulnerabilities associated with tau aggregation using any CRISPR Cas system as claimed was nascent at the time of filing of the instant application. The prior art does not teach said screening assay using any fused to one or more transcriptional activation domains, a chimeric adaptor protein fused to any of one or more transcriptional activation, any tau repeat domain and a vast genus of guide RNAs.
Nathaniel et al. ("Elucidating Cellular Trafficking Pathways Controlling Prion-like Spread of au Aggregation Using CRISPR Interference Screens [abstract]," Abstracts; Poster Presentations, Cell Biology 2016, ASCB Annual Meeting, P887, 2016, see IDS 12/20/2023) teach CRISPR interference (CRISPRi)-based platform for genetic screens to elucidate tau aggregation, wherein the CRISPRi enables knockdown of endogenous genes by the dCas9 endonuclease fused to a transcriptional repressor domain with single guide RNAs, and a human FRET based tau aggregation reporter cell line is exposed to preformed tau fibrils (no details on actual methods are given). There is no teaching or suggestion in the prior art directed to a method of screening for genetic vulnerabilities of tau aggregation as claimed.
The level of one of ordinary skill:
While the level of one of ordinary skill practicing said invention would be high, the level of predictability is considered variable as evident in the prior art discussed above and is not considered to provide sufficient enablement to practice the claimed invention.
Because the state of the prior art does not provide evidence of the degree of predictability that using the screening method as broadly claimed would function to identify genetic vulnerabilities associated with tau aggregation in any cell type or species, one of ordinary skill in the art would look for guidance or direction in the instant specification.
The level of predictability in the art:
“The “predictability or lack thereof” in the art refers to the ability of one skilled in the art to extrapolate the disclosed or known results to the claimed invention. If one skilled in the art can readily anticipate the effect of a change within the subject matter to which the claimed invention pertains, then there is predictability in the art. On the other hand, if one skilled in the art cannot readily anticipate the effect of a change within the subject matter to which that claimed invention pertains, then there is lack of predictability in the art. Accordingly, what is known in the art provides evidence as to the question of predictability.” (MPEP 2164.03).
The amount of direction provided by the inventor:
The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The “amount of guidance or direction” refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, 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).
The existence of working examples:
The working embodiment in the instant application describes methods of screening for genetic vulnerabilities associated with tau aggregation using a CRISPR Streptococcus pyogenes Cas9 assay, Tau biosensor cells in HEK293T stably expressing Tau four-repeat domain and a select number of guide RNAs. The working embodiment in the instant application does not include experiments demonstrating the breadth of the claimed method. Even Applicants own work describes limitations with the method as claimed. (see Prissette et al. "Disruption of nuclear envelope integrity as a possible initiating event in tauopathies." Cell Reports 40.8 (2022): 111249 of record IDS 12/20/2023). Applicant describes on page 9 that screening was limited by the gRNA library in that not all gRNAs were capable of inactivating their target genes with high efficiency. Applicant further cautions that it is unknown whether the genetic vulnerabilities of the identified modifiers represent a true tau pathology because this system has not been tested in a tauopathy disease relevant model (see also page 9).
The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success. A patent is granted for a completed invention, not the general suggestion of an idea (MPEP 2164.03 and Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1325-26 (Fed. Cir. 2004).
While the MPEP 2164.02 states the specification need not contain an example if the invention is otherwise disclosed in such manner that one skilled in the art will be able to practice it without an undue amount of experimentation. In re Borkowski, 422 F.2d 904, 908, 164 USPQ 642, 645 (CCPA 1970), the lack of a working example, however, is a factor to be considered, especially in a case involving an unpredictable and undeveloped art.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
Without further guidance, one of skill in the art would have to practice a substantial amount of trial and error experimentation to determine how the screening assay performs using any Cas protein, any tau repeat domain, specific gRNA libraries and in any cell type which correlates with an actual disease model to predictably identified genetic vulnerabilities associated with tau aggregation.
Claims Free of the Prior Art
The prior art does not teach or make obvious the claimed method of screening for genetic vulnerabilities of tau aggregation. The closest prior art is Nathaniel et al. ("Elucidating Cellular Trafficking Pathways Controlling Prion-like Spread of au Aggregation Using CRISPR Interference Screens [abstract]," Abstracts; Poster Presentations, Cell Biology 2016, ASCB Annual Meeting, P887, 2016, see IDS 12/20/2023) who teach CRISPR interference (CRISPRi)-based platform for genetic screens to elucidate tau aggregation, wherein the CRISPRi enables knockdown of endogenous genes by the dCas9 endonuclease fused to a transcriptional repressor domain with single guide RNAs, and a human FRET based tau aggregation reporter cell line is exposed to preformed tau fibrils (no details on actual methods are given).
Nathaniel et al. do not teach using the methods to screen for genetic vulnerabilities associated with tau aggregation comprising the steps (a) – (c) in claim 1. Therefor the claim is novel and unobvious over the prior art
The sequences 11, 17, 33 and 36-39 are free of the prior art in the context of the claims.
SEQ ID No. 11: the prior art does not teach a sequence comprising SEQ ID No. 11 or teach it would be obvious to make a chimeric Cas protein fused to SEQ ID No. 11 which is linked to a first report as claimed.
SEQ ID No. 17: the prior art does not teach a sequence comprising residues 13-16 and 53-56 of SEQ ID No. 17 or teach it would be obvious to make an oligonucleotide encoding a chimeric Cas protein as claimed.
SEQ ID No. 33: the prior art does not teach a sequence comprising SEQ ID No. 36 or teach it would be obvious to make an adaptor-binding element within the second loop of each guide RNA as claimed.
SEQ ID No. 36: the prior art does not teach a sequence comprising SEQ ID No. 36 or teach it would be obvious to make an oligonucleotide encoding a chimeric Cas protein as claimed.
SEQ ID No. 37: Patent No.11578312 teach SEQ ID No 469 which is identical to SEQ ID No. 37 but does not teach or make obvious using this sequence in the claimed methods.
Query Match 100.0%; Score 2408; Length 473;
Best Local Similarity 100.0%;
Matches 473; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
SEQ ID No. 38: the prior art does not teach a sequence comprising SEQ ID No. 38 or teach it would be obvious to make an oligonucleotide encoding a chimeric Cas protein as claimed.
SEQ ID No. 39: Patent No.10,550,372 teach SEQ ID No 469 which is identical to SEQ ID No. 39 but does not teach or make obvious using this sequence in the claimed methods.
Query Match 100.0%; Score 1419; Length 1419;
Best Local Similarity 100.0%;
Matches 1419; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kimberly Chong at (571)272-3111. The examiner can normally be reached Monday thru Friday between M-F 8:00am-4:30pm.
If attempts to reach the examiner by telephone are unsuccessful please contact the SPE for 1636 Neil Hammell at 571-272-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KIMBERLY CHONG/
Primary Examiner Art Unit 1636
Prosecution Insights