DETAILED ACTION
Status of the Application
Claims 67-83 are pending.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s election without traverse of Group I, claims 67-75, drawn to a method for producing a human clotting factor, and the election of the combination of FII and fibrinogen, the guide RNA of SEQ ID NO: 8 and the aptamer MS2, as submitted in a communication filed on 6/2/2026 is acknowledged.
Claims 76-83 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 6/2/2026.
Claim 67-75 are at issue and are being examined to the extent they encompass the elected invention.
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed. The claims are not directed to a composition comprising recombinant human clotting factors. Appropriate correction is required.
Priority
Acknowledgment is made of a claim for domestic priority under 35 U.S.C. 119(e) to provisional application No. 63/266,532 filed on 01/07/2022.
This is the US national application which entered the national stage from PCT/US2023/060222 filed on 01/06/2023.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 7/12/2024 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings submitted on 7/3/2024 have been reviewed and are accepted by the Examiner for examination purposes.
Claim Objections
Claims 67-68 are objected to due to the recitation of “FII”, “FVII”, “FIX”, and “FX”. Abbreviations unless otherwise obvious and/or commonly used in the art, should not be recited in the claims without at least once reciting the entire phrase for which the abbreviation is used. Appropriate correction is required.
Claim 67 is objected to due to the recitation of “a nucleotide sequence encoding a catalytically inactive Type II Cas9 protein engineered to bind but cleave DNA a DNA/RNA complex”. To enhance clarity, the term should be amended to recite “a nucleotide sequence encoding a catalytically inactive Type II Cas9 protein engineered to bind the guide RNA but not cleave DNA”. Appropriate correction is required.
Claim 72 is objected to due to the recitation of “SEQ ID NOs: 8-63“. The term should be amended to recite “SEQ ID NO: 8-63“. Appropriate correction is required.
Claim 73 is objected to due to the recitation of “wherein the aptamer stem loop is a MS2 aptamer….” for the following reasons. A stem loop is the structure that the aptamer can form. Therefore, to enhance clarity and to be consistent with the language of claim 67, the term should be amended to recite “wherein the aptamer is a MS2 aptamer…”. Correction is required.
Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA )
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 67-75 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 pre-AIA the applicant regards as the invention.
Claim 67 (claims 68-75 dependent thereon) is indefinite in the recitation of “expressing a clotting factor from a clotting factor encoding polynucleotide in an engineered…system in a human hepatocyte cell, wherein said clotting factor is FII….or fibrinogen, and wherein said CRISPR-SAM system comprises a first regulatory element operable in the human hepatocyte cell operably linked to a guide polynucleotide encoding a CRISPR-CAS system guide RNA that hybridizes to the clotting factor encoding polynucleotide and a second regulatory element operable in the human hepatocyte cell operably linked to a SAM encoding polynucleotide, wherein said SAM encoding polynucleotide comprises a nucleotide sequence encoding a catalytically inactive Type II Cas9 protein….and a nucleotide sequence encoding a transcriptional activation domain and an aptamer capable of forming a RNA aptamer stem loop in the guide RNA by specifically hybridizing to the human clotting factor polynucleotide…” for the following reasons.
As written, it is unclear if the claim requires the CRISPR-SAM system to have a polynucleotide encoding the clotting factor or if the polynucleotide encoding the clotting factor is endogenous to the hepatocyte cell and already present in the hepatocyte cell. For examination purposes, it will be assumed that the CRISPR-SAM system does not have a polynucleotide encoding the clotting factor and it will be assumed that the polynucleotide encoding the clotting factor is an endogenous gene in the hepatocyte cell encoding the clotting factor.
In addition, as written, it is unclear as to how the SAM polynucleotide can comprise a nucleotide sequence encoding an aptamer separately from the guide RNA if the guide RNA that hybridizes to the human clotting factor polynucleotide is the one that has the aptamer stem loop. One of skill in the art would assume based on the teachings of the specification that the aptamer is part of the guide RNA which forms a stem loop structure. As such, a polynucleotide that encodes the aptamer should be part of the polynucleotide that encodes the guide RNA that hybridizes to the human clotting factor polynucleotide. If, in fact, the claim requires a separate polynucleotide encoding an aptamer which is not one that encodes the guide RNA that hybridizes to the human clotting factor polynucleotide, it is unclear if the claim requires a nucleotide sequence encoding a separate guide RNA from the guide RNA previously indicated in the claim (e.g., “a first regulatory element operable in the human hepatocyte cell operably linked to a guide polynucleotide encoding a CRISPR-CAS system guide RNA that hybridizes to the clotting factor encoding polynucleotide”). Also, it is noted that the claim refers to a “clotting factor encoding polynucleotide” as well as a “human clotting factor polynucleotide”, thus being unclear if these terms are being used interchangeably. For examination purposes, it will be assumed that the “human clotting factor polynucleotide” refers to the “clotting factor encoding polynucleotide”. Also, no patentable weight will be given to the term “and an aptamer capable of forming a RNA aptamer stem loop in the guide RNA by specifically hybridizing to the human clotting factor polynucleotide”. It will be assumed that the claim requires a first regulatory element operable in the human hepatocyte cell operably linked to a guide polynucleotide encoding a CRISPR-CAS system guide RNA that hybridizes to the clotting factor encoding polynucleotide, wherein said CRISPR-CAS system guide RNA comprises an aptamer that is able to form an stem loop in said guide RNA. Correction is required.
Claim 68 is indefinite in the recitation of “…a) more than one clotting factor is expressed and recovered from the human hepatocyte cell…d) each of FII….and FX are expressed in different human hepatocyte cells and then combined…” for the following reasons. First, it is unclear if in part a) of claim 68, the claim requires production of other clotting factors beyond FII, FVII, FIX, FX or fibrinogen. Second, it is unclear as to how part d) further limits claim 67 in view of the fact that the method of claim 67 requires a particular hepatocyte cell that comprises a CRISPR-SAM system, and part d) requires hepatocytes which produce any of the recited clotting factors in hepatocytes which are not those of the method of claim 67 (different human hepatocyte cells). For examination purposes, no patentable weight will be given to parts a) and d). Correction is required.
Claim 71 is indefinite in the recitation of “wherein the polynucleotide encoding the Cas9 protein and the polynucleotide encoding the guide RNAs do not naturally occur together” for the following reasons. As known in the art, Cas9 proteins are endogenous to bacterial and archaeal species. The guide RNAs of claim 67 are guide RNAs that would target polynucleotides that encode clotting factors. It is not believed that bacteria or archaea naturally produce clotting factors. Therefore, the guide RNAs of claim 67 and the Cas9 protein of claim 67 do not naturally occur together. As such, it is unclear as to how claim 71 further limits claim 67. Claim 71 will be interpreted as a duplicate of claim 67. Correction is required.
Claims 72 and 74 are indefinite in the recitation of “RNA comprises a nucleic acid sequence of any one of SEQ ID NO: 8-63” and “aptamer stem loop comprises a nucleic acid sequence of any one of SEQ ID NO: 1-7” for the following reasons. The term “a nucleic acid sequence” can be interpreted as a fragment within the nucleic acid sequence of any one of SEQ ID NO: 8-63 or SEQ ID NO: 1-7 due to the recitation of “a”. Therefore, it is unclear if (a) the RNA is required to comprise a fragment of any one of SEQ ID NO: 8-63 or if the RNA is required to comprise the amino acid sequence of any one of SEQ ID NO: 8-63, and (b) the aptamer stem loop is required to comprise a fragment of any one of SEQ ID NO: 1-7 or if the aptamer stem loop is required to comprise the amino acid sequence of any one of SEQ ID NO: 1-7. If the intended limitation is “comprises the nucleic acid sequence of any one of SEQ ID NO: X-Y”, the claims should be amended accordingly. Correction is required.
Claim 75 is indefinite in the recitation of “wherein the hepatocyte cell is a HEK293 cell” for the following reasons. As known in the art, a HEK293 cell is a derivative of a human embryonic kidney (HEK) cell while a hepatocyte is a liver cell. Therefore, it is unclear as to how a human embryonic kidney cell can be a liver cell. The scope of claim 75 is not encompassed by the scope of claim 67. Therefore, claim 74 is not a proper dependent claim. Correction is required.
Claims 67-75 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. While the preamble states that the claimed invention is a method of producing a recombinant human clotting factor from a human hepatocyte cell that requires a CRISPR-SAM system, there is no step indicating how the CRISPR-SAM system is involved in the production of the recombinant human clotting factor, or a step where the hepatocyte cell is cultured so that the clotting factor is made. Please note that as currently presented, there is no step of transfecting the human hepatocyte cell with the CRISPR-SAM system. Moreover, as interpreted, the hepatocyte cell already has the polynucleotide encoding the human clotting factor because the hepatocyte has an endogenous gene encoding the clotting factor. Therefore, even if one assumes that the claimed method requires the culturing of the hepatocyte cell, the cell would endogenously produce the clotting factor, regardless of the CRISPR-SAM system recited. If the intended method is one where the system is introduced into the hepatocyte cell, the claims should be amended accordingly. Correction is required.
When amending the claims, applicant is advised to carefully review all examined claims and make the necessary changes to ensure proper antecedent basis and dependency.
Claim Rejections - 35 USC § 112(d) or Fourth Paragraph (pre-AIA )
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.
Claim 75 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 75 is directed to a method that requires a HEK293 cell (kidney cell). However, claim 67 from which claim 75 depends, is directed to a method that requires a hepatocyte cell. Therefore, claim 75 fails to further limit the subject matter of the claim from which it depends because a HEK293 cell cannot further limit a hepatocyte cell. 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. Correction is required.
Claim Rejections - 35 USC § 112(a) or First Paragraph (pre-AIA )
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 67-75 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.
As stated in MPEP 2111.01, during examination, the claims must be interpreted as broadly as their terms reasonably allow. Claims 67-75 are directed in part to a method for the production of a human clotting factor, wherein the clotting factor is factor II, factor VII, factor IX, factor X or fibrinogen, wherein said method requires polynucleotides encoding a genus of catalytically inactive Cas9 proteins, transcriptional activation domains, guide RNAs and aptamers having any structure, wherein said aptamers are introduced anywhere within the guide RNAs, wherein the guide RNAs hybridize to a polynucleotide encoding the human clotting factor. See Claim Rejections under 35 USC § 112(b) or Second Paragraph (pre-AIA ) for claim interpretation.
In University of California v. Eli Lilly & Co., 43 USPQ2d 1938, the Court of Appeals for the Federal Circuit has held that “A written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as by structure, formula, [or] chemical name,’ of the claimed subject matter sufficient to distinguish it from other materials”. As indicated in MPEP § 2163, the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or 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 that Applicant was in possession of the claimed genus. In addition, MPEP § 2163 states that 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.
There is no structural limitation with respect to the members of the genus of catalytically inactive Cas9 proteins, transcriptional activation domains, guide RNAs and aptamers encoded by the recited polynucleotides. While the specification in the instant application discloses the structure of a single catalytically inactive Cas9 protein (dCas9 from S. pyogenes), a single transcription activator domain which is the viral particle 64 (VP64), a few number of guide RNAs that hybridize to genes encoding the human clotting factor, a limited number of aptamers that would bind peptides that can be fused to the heat shock factor 1 (HSF1) and the nuclear factor NF-kappa-B-p65 subunit (p65), and a limited number of locations within a guide RNA where the aptamer can be incorporated to the guide RNA such that HSF1 and/or p65 can bind via said peptides to the aptamer without disrupting the Cas9/guide RNA complex, the specification is silent with regard to the structural features required in any Cas9 protein, the structural features required in any catalytically inactive Cas9 protein, or the structural features required in any transcriptional activation domain that could be used to activate the transcription of any gene encoding the recited clotting factors in a hepatocyte. In addition, the specification does not provide the structural features required in any aptamer that can be used to enhance transcription of a gene encoding a clotting factor. No disclosure of a structure/function correlation has been provided which would allow one of skill in the art to envision the structure of any catalytically inactive Cas9 protein, any transcriptional activation domain that could be used to activate the transcription of any gene encoding the human clotting factor recited, as well as any guide RNs and aptamer that could be used together to bind any factor that can enhance transcription.
The claims encompass a large genus of polynucleotides encoding proteins, guide RNAs and aptamers which are structurally unrelated. A sufficient written description of a genus of polypeptides and polynucleotides may be achieved by a recitation of a representative number of polypeptides and polynucleotides defined by their amino acid or nucleic acid sequence or a recitation of structural features common to members of the genus, which features constitute a substantial portion of the genus. However, in the instant case, there is no recited structural feature which is representative of all the members of the genus of proteins, guide RNAs and aptamers recited, or a correlation between structure and function which would provide those unknown structural features. Furthermore, while one could argue that the few species disclosed are representative of the structure of all the members of the genus of proteins encoded by the recited polynucleotides, it is noted that the art teaches several examples of how even highly structurally homologous polypeptides can have different activities. For example, Witkowski et al. (Biochemistry 38:11643-11650, 1999) teach that one conservative amino acid substitution transforms a β-ketoacyl synthase into a malonyl decarboxylase and completely eliminates β-ketoacyl synthase activity. Tang et al. (Phil Trans R Soc B 368:20120318, 1-10, 2013) teach that two Dehalobacter reductive dehalogenases, CfrA and DcrA, having 95.2% sequence identity to teach other have exclusively different substrate (Abstract; page 7, left column, Discussion, CfrA and DcrA). Seffernick et al. (J. Bacteriol. 183(8):2405-2410, 2001) teach that two naturally occurring Pseudomonas enzymes having 98% amino acid sequence identity catalyze two different reactions: deamination and dehalogenation, therefore having different function. Therefore, since minor structural differences may result in changes affecting function, and no additional information correlating structure with the desired functional characteristics has been provided, one cannot reasonably conclude that the few species disclosed are representative of the structure of all the proteins encoded by the polynucleotides required by the claims.
Due to the fact that the specification only discloses a limited number of species of the genus of proteins, guide RNAs and aptamers encoded by the recited polynucleotides, and the lack of description of any additional species by any relevant, identifying characteristics or properties, one of skill in the art would not recognize from the disclosure that Applicant was in possession of the claimed invention.
Claims 67-75 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 a method for producing a human clotting factor, wherein said clotting factor is factor II, factor VII, factor IX, factor X or fibrinogen, wherein said method comprises culturing a HEK293 cell transfected with a plasmid that encodes a guide RNA that comprises an aptamer that comprises SEQ ID NO: 1, wherein the guide RNA also comprises SEQ ID NO: 8, a plasmid encoding a fusion protein that comprises a S. pyogenes dCas9 protein and viral particle 64 (VP64), and a plasmid that encodes a fusion protein that comprises heat shock factor 1 (HSF1), the nuclear factor NF-kappa-B-p65 subunit (p65), and a dimerized MS2 bacteriophage coat protein, does not reasonably provide enablement for a method for producing a human clotting factor in a human hepatocyte cell, wherein the human clotting factor is factor II, factor VII, factor IX, factor X or fibrinogen, wherein said method requires polynucleotides encoding any catalytically inactive Cas9 protein, any transcriptional activation domain, any guide RNA and aptamers having any structure, wherein said aptamers are introduced anywhere within the guide RNAs, wherein the guide RNA hybridize to a polynucleotide encoding the human clotting factor. 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/or use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 737, 8 USPQ2nd 1400 (Fed. Cir. 1988)) as follows: 1) quantity of experimentation necessary, 2) the amount of direction or guidance presented, 3) the presence and absence of working examples, 4) the nature of the invention, 5) the state of prior art, 6) the relative skill of those in the art, 7) the predictability or unpredictability of the art, and 8) the breadth of the claims. The factors which have led the Examiner to conclude that the specification fails to teach how to make and/or use the claimed invention without undue experimentation, are addressed in detail below.
The breadth of the claims. Claims 67-75 broadly encompass a method for producing a human clotting factor in a human hepatocyte cell, wherein the human clotting factor is factor II, factor VII, factor IX, factor X or fibrinogen, wherein said method requires polynucleotides encoding any catalytically inactive Cas9 protein, any transcriptional activation domain, any guide RNA and aptamers having any structure, wherein said aptamers are introduced anywhere within the guide RNA, wherein the guide RNA hybridize to a polynucleotide encoding the human clotting factor. See Claim Rejections under 35 USC § 112(b) or Second Paragraph (pre-AIA ) for claim interpretation.
The enablement provided is not commensurate in scope with the claims due to the extremely large number of polynucleotides encoding proteins, guide RNAs and aptamers of unknown structure encompassed by the claims, and the lack of information regarding the structural elements required in catalytically inactive Cas9 proteins, transcriptional activation domains, guide RNAS, aptamers and proteins that can be bind to the aptamers to increase the transcription of genes encoding human clotting factors. In the instant case, the specification enables a method for producing a human clotting factor, wherein said clotting factor is factor II, factor VII, factor IX, factor X or fibrinogen, wherein said method comprises culturing a HEK293 cell transfected with a plasmid that encodes a guide RNA that comprises an aptamer that comprises SEQ ID NO: 1, wherein the guide RNA also comprises SEQ ID NO: 8, a plasmid encoding a fusion protein that comprises a S. pyogenes dCas9 protein and viral particle 64 (VP64), and a plasmid that encodes a fusion protein that comprises heat shock factor 1 (HSF1), the nuclear factor NF-kappa-B-p65 subunit (p65), and a dimerized MS2 bacteriophage coat protein.
The amount of direction or guidance presented and the existence of working examples. The specification discloses the structure of a single catalytically inactive Cas9 protein (dCas9 from S. pyogenes), a single transcription activator domain which is the viral particle 64 (VP64), a limited number of guide RNAs that hybridize to genes encoding the human clotting factor, a limited number of aptamers that would bind certain peptides that could be fused to the heat shock factor 1 (HSF1) and the nuclear factor NF-kappa-B-p65 subunit (p65), and a limited number of locations within a guide RNA where the aptamer can be incorporated to the guide RNA such that HSF1 and/or p65 can bind to the aptamer via said peptides without disrupting the Cas9/guide RNA complex. However, the specification fails to provide the structural features required in any Cas9 protein, the structural features required in any catalytically inactive Cas9 protein, or the structural features required in any transcriptional activation domain that could be used to activate the transcription of any gene encoding the recited clotting factors in a hepatocyte cell. There is no disclosure of the structural features required in any aptamer that could be used to enhance transcription of a gene encoding a clotting factor. No disclosure of a structure/function correlation has been provided which would allow one of skill in the art to envision the structure of any catalytically inactive Cas9 protein, any transcriptional activation domain that could be used to activate the transcription of any gene encoding the human clotting factor recited, as well as any guide RNs and aptamer that could be used together to bind any factor that can enhance transcription.
The state of prior art, the relative skill of those in the art, and the predictability or unpredictability of the art. The nucleotide sequence of a polynucleotide determines the structure and functional properties of the protein or RNA encoded by said polynucleotide. While the art discloses a limited number of catalytically inactive Cas9 proteins, transcriptional activation domains, aptamers and peptides that bind those aptamers, neither the specification nor the art provide a correlation between structure and function such that one of skill in the art can envision the structure of any catalytically inactive Cas9 protein, transcriptional activation domain, aptamer and peptide that can bind said aptamer. The art clearly teaches that (a) determining function based solely on structural homology, and (b) modification of a protein’s amino acid sequence to obtain the desired activity without any guidance/knowledge as to which amino acids in a protein are tolerant of modification and which ones are conserved are highly unpredictable. For example, Singh et al. (Current Protein and Peptide Science 19(1):5-15, 2018) disclose different protein engineering approaches and state that despite the availability of an ever-growing database of protein structures and highly sophisticated computational algorithms, protein engineering is still limited by the incomplete understanding of protein functions, folding, flexibility and conformational changes (page 11, left column, last paragraph). Sadowski et al. (Current Opinion in Structural Biology 19:357-362, 2009) teach that much of the problem in assigning function from structure comes from functional convergence, where although a stable structure is required to perform many functions it is not always necessary to adopt a particular structure to carry out a particular function (page 357, right column, first full paragraph). Sadowski et al. further explain that the unexpected and significant difficulties of predicting function from structure show that the potential of structural models for providing novel functional annotations has not yet fully realized. Sadowski et al. also states that while a few successes have been achieved which required manual intervention, the ability to vary the requirements for specificity in prediction means that it is difficult to determine how useful the end result may be for the user (page 361, left column, first full paragraph). The teachings of Singh et al. and Sadowski et al. are further supported by the teachings of Witkowski et al., Tang et al. and Seffernick et al. already discussed above, where it is shown that even small amino acid changes result in activity changes.
The quantity of experimentation required to practice the claimed invention based on the teachings of the specification. While methods of generating or isolating variants of a polynucleotide/polypeptide and assays were known in the art at the time of the invention, it was not routine in the art to screen by a trial and error process for an essentially infinite number of proteins to find Cas9 proteins and catalytically inactive variants thereof, or transcriptional activation domains that could be used to activate transcription of endogenous genes encoding human clotting factors in human hepatocytes. Similarly, it was not routine in the art to screen by a trial and error process for any aptamer and the peptide that can bind to it. In the absence of (i) a rational and predictable scheme for selecting those polynucleotides most likely to encode proteins or RNAs having the desired functional features, and/or (ii) a correlation between structure and function, one of skill in the art would have to test an essentially infinite number of (a) polynucleotides that encode the recited proteins, and (b) peptides to find those that can bind to any aptamer.
Therefore, taking into consideration the extremely broad scope of the claim, the lack of guidance, the amount of information provided, the lack of knowledge about a correlation between structure and the desired function, and the high degree of unpredictability of the prior art in regard to structural changes and their effect on function, one of ordinary skill in the art would have to go through the burden of undue experimentation in order to practice the claimed invention. Thus, Applicant has not provided sufficient guidance to enable one of ordinary skill in the art to make and use the invention in a manner reasonably correlated with the scope of the claims.
Art of Interest
Konermann et al. (Nature 517:583-588, 2015; cited in the IDS) disclose transcriptional activation by an engineered CRISPR-Cas9 complex for genome scale gain of function perturbations at endogenous loci (page 583, left column, first paragraph), wherein the complex comprises (i) a dCas9-VP64, or a dCas9-p65 fusion, and (ii) a guide RNA that comprises an aptamer that is able to bind a dimerized MS2 bacteriophage coat protein, wherein the complex is able to bind a MS2 -VP64, MS2-p65, or a MS2-p65-HSF1 fusion (page 584, right column, second full paragraph). Konermann et al. used this transcriptional activation system to find genes that upon activation confer resistance to a BRAF inhibitor (Abstract; page 586, left column). Konermann et al. teach that their system (SAM) can be used for genome-scale gene activation screening (page 586, left column). Konermann et al. do not teach whether their system can be as effective as a viral promoter for recombinant protein expression. Correa de Freitas et al. (Protein Expression and Purification 137:26-33, 2017) discloses the successful production of high levels of recombinant factor VII in human cell lines Sk-Hep-1 and HepG2 (liver cells) transfected with a lentiviral vector encoding the human factor VII (page 27, Materials and Methods). Bonfim et al. (Biotechnology Letters 43:143-152, 2021) teach that Sk-Hep-1 is an effective human cell line that has been successfully used for the production of factor VIII and FIX (page 144, right column, fourth full paragraph).
Conclusion
No claim is in condition for allowance.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to DELIA M RAMIREZ, Ph.D., whose telephone number is (571) 272-0938. The examiner can normally be reached on Monday-Friday from 8:30 AM to 5:00 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert B. Mondesi, can be reached at (408) 918-7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
/DELIA M RAMIREZ/Primary Examiner, Art Unit 1652
DR
July 23, 2026
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