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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 4, 2026 has been entered.
Detailed Action
This action is in response to the papers filed March 4, 2026.
Amendments
Applicant's response and amendments, filed March 4, 2026, to the prior Office Action is acknowledged. Applicant has cancelled Claims 1-119, 121-123, 126-127, and 139, and amended Claims 120 and 137.
Claims 120, 124-125, and 128-138 are pending and under examination.
Priority
This application is a continuation of application 16/839,164 filed on April 3, 2020, now abandoned, which is a continuation of application 15/985,658 filed on May 21, 2018, now abandoned.
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d). Certified copies of foreign patent application GB 1808063.0 filed May 17, 2018, and GB1719896.1 filed November 29, 2017 are provided with application 16/839,164.
Information Disclosure Statement
Applicant has filed an Information Disclosure Statement on March 4, 2026 that has been considered.
The signed and initialed PTO Forms 1449 are mailed with this action.
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.
1. Claims 120, 124-125, and 128-138 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 120 and 137 have been amended to incorporate the limitations of prior Claims 123 and 129, now reciting a Cas nuclease and/or a crRNA or a gRNA that is operably with a Cas in a target bacterial cell.
Claims 124 and 126 recite a Cas that is operable in a target bacterial cell.
The claims denote that not all of the crRNAs, gRNAs, and Cas nucleases are able to achieve the functional property(ies) of being operable in the enormously broad genus of “(target) bacterial cells”, individually and/or in combination(s) and/or subcombination(s) thereof, respectively.
The claims are considered to lack adequate written description for encompassing an enormously vast genus of crRNA molecules, gRNA molecules, and Cas nucleases for which neither the claims recite, nor the specification discloses, the structure/function nexus between the enormously vast genus of structurally undisclosed claimed crRNA molecules and/or gRNA molecules that are to be operable with the vast genus of Cas nucleases such that the enormously vast genus of crRNA/Cas and/or gRNA/Cas complexes are necessarily and predictably operable in the enormously vast genus of biologically different “(target) bacteria”.
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 encompass an enormously vast genus of target bacterial cell species (specification, pgs 84-113, Table 1).
The claims encompass an enormous genus of Cas nucleases molecules [0064], including, but not limited to, Type I Cas, Type II Cas, Type III Cas, Type IV Cas, Type V Cas, Cas 3, Cas9, Cpf, CasX, and CasY nucleases that are to have the functional property of being operable in one or more of the enormously vast genus of target bacterial cell species.
Terns et al (U.S. 2011/0189776) disclosed that bacterial genomes naturally comprise a multitude of different Cas-type enzymes (e.g. Figure 5F, at least 29 different Cas-type enzyme loci), not all of which have actually been functionally characterized.
Doudna et al (U.S. 2016/0060653) is considered relevant prior art for having disclosed Cas nucleases, wherein the amino acid sequence of the Cas nuclease may have as little as 75% identity to a reference nuclease (e.g. [0198]).
SEQ ID NO:993 is 1688 amino acids in length.
75% identity allows for as many as 422 amino acid changes, 20^422, which is essentially an infinite genus.
(https://www.calculator.net/exponent-calculator.html; last visited November 5, 2024)
Thus, the breadth of the claimed genus of Cas-type nuclease encompasses an essentially infinite genus of structurally undisclosed Cas-type nucleases.
The claims encompass an enormously vast genus of structurally undisclosed crRNA molecules that are to have the functional property of being operable in one or more of the enormously vast genus of target bacterial cell species.
Goldberg et al (Conditional tolerance of temperate phages via transcription-dependent CRISPR-Cas targeting, Nature 514: 633-637, (and Supplementary Materials), 18 pages total, 2014) is considered relevant prior art for having taught a bacterial crRNA nucleotide sequence that binds to the corresponding target nucleotide sequence that is to be edited by the Cas nuclease, wherein the crRNA binding sequences is at least 35 nucleotides in length (Figure 1a).
Thus, the breadth of the claimed genus of crRNA binding sequences is 4^35 = about 1x10^21 structurally undisclosed crRNA sequences.
(https://www.calculator.net/exponent-calculator.html; last visited November 5, 2024)
The claims encompass an enormously vast genus of structurally undisclosed guide RNA molecules that are to have the functional property of being operable in one or more of the enormously vast genus of target bacterial cell species.
Doudna et al also disclosed a guide RNA nucleotide sequence that binds to the corresponding target nucleotide sequence that is to be edited by the Cas nuclease, wherein the gRNA binding sequences is at least 100 nucleotides in length (e.g. [0169]).
Thus, the breadth of the claimed genus of gRNA binding sequences is 4^100 = about 1x10^60 structurally undisclosed gRNA sequences.
The claims encompass an enormously vast genus of structurally undisclosed guide RNA molecules that are to have the functional property of being operable with the essentially vast genus of Cas-type nucleases.
Doudna et al also disclosed that the gRNA molecule comprises a nucleotide sequence that binds to the Cas-type nuclease (e.g. [0172], Protein-Binding Segment of a DNA-targeting RNA), wherein the protein-binding segment may be up to 100 nucleotides in length (e.g. [0187]). Artificial sequences may share very little (roughly 50% identity) with naturally-occurring tracrRNAs and crRNAs [0186].
Thus, the breadth of the claimed genus of Cas-type nuclease protein-binding segments of the gRNA is 4^100 = about 1x10^60 structurally undisclosed gRNA protein-binding segment sequences.
The limitation(s) “operable…with a Cas nuclease in the target bacterial cell” and “operable in a target bacterial cell” merely state(s) a functional characteristic without providing any indication about how the functional characteristic is provided.
The claims fail to recite, and the specification fails to disclose, a nexus between the essentially infinite genus of structurally and functionally undisclosed Cas-type nucleases and the corresponding enormously vast genus of biologically different (target) bacterial species so as to necessarily and predictably achieve operable gene-editing functional properties within the enormously vast genus of biologically different (target) bacterial species.
The claims fail to recite, and the specification fails to disclose, a first Cas-type nuclease, or variant thereof, from the essentially infinite genus of structurally and functionally undisclosed Cas-type nucleases that is necessarily and predictably operable to achieve gene-editing functional properties within a first (target) bacterial species, e.g. Flavobacterium flevense, but not a second (target) bacterial species, e.g. Pectobacterium aroidearum, for example.
The claims fail to recite, and the specification fails to disclose, how to transform or otherwise modify a first Cas-type nuclease, or variant thereof, from the essentially infinite genus of structurally and functionally undisclosed Cas-type nucleases that is unable to achieve gene-editing functional properties within a first (target) bacterial species, e.g. Ureibacillus terrenus, into a second Cas-type nuclease that now, is necessarily and predictably able to achieve gene-editing functional properties within said first (target) bacterial species, for example.
The claims fail to recite, and the specification fails to disclose, a nexus between the enormously vast genus of 1x10^21 structurally undisclosed crRNA sequences and the corresponding essentially infinite genus of structurally and functionally undisclosed Cas-type nucleases so as to necessarily and predictably achieve operable gene-editing functional properties within the enormously vast genus of biologically different (target) bacterial species.
The claims fail to recite, and the specification fails to disclose, a nexus between the enormously vast genus of 1x10^60 structurally undisclosed gRNA DNA-target sequences, the enormously vast genus of 1x10^60 structurally undisclosed gRNA Cas protein-binding sequences, and the corresponding essentially infinite genus of structurally and functionally undisclosed Cas-type nucleases so as to necessarily and predictably achieve operable gene-editing functional properties within the enormously vast genus of biologically different (target) bacterial species.
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 crRNA sequence and/or gRNA are to bind to a Cas-type nuclease to thereby form a complex does not tell you anything at all about the structure (nucleotide sequences) of the enormously vast genus of about 1x10^21 structurally undisclosed crRNA sequences, the enormously vast genus of 1x10^60 structurally undisclosed gRNA DNA-target sequences, and the enormously vast genus of 1x10^60 structurally undisclosed gRNA Cas protein-binding sequences, that will necessarily and predictably bind, and thus complex with, the essentially infinite genus of structurally and functionally undisclosed Cas-type nuclease variants encompassed by the claims that necessarily and predictably achieve operable gene-editing functional properties within the enormously vast genus of biologically different (target) bacterial species.
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 claims encompass:
an enormously vast genus of about 1x10^21 structurally undisclosed crRNA sequences;
an enormously vast genus of 1x10^60 structurally undisclosed gRNA DNA-target sequences;
an enormously vast genus of 1x10^60 structurally undisclosed gRNA Cas protein-binding sequences;
an essentially infinite genus of structurally and functionally undisclosed Cas-type nuclease variants; and
an enormously vast genus of biologically different (target) bacterial species (pgs 84-113, Table 1).
“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.
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.
The Examiner suggests cancellation of the phrases:
“wherein the crRNA or gRNA is operable with a Cas in a target bacterial cell” (Claims 123 and 139);
“wherein the crRNA or gRNA guides the Cas to a target nucleic acid sequence in the target bacterial cell to modify the target nucleic acid sequence” (Claim 123);
“the engineered nucleic acid encodes a Cas that is operable in a target bacterial cell to
modify a target nucleic acid sequence comprised by the target bacterial cell” (Claim 126); and
“operable in a target bacterial cell to modify a target nucleic acid sequence comprised by the target bacterial cell”.
Response to Arguments
Applicant argues that the claims are not directed to CRISPR/Cas systems per se, but rather a method of producing non-self-replicative transduction particles.
Applicant’s argument(s) has been fully considered, but is not persuasive. The claims literally recite CRISPR/Cas systems at a high level of generality, and encompass an essentially infinite genus of structurally and functionally undisclosed Cas-type nuclease variants, for which the art (Terns et al) taught that not all of the multitude of different Cas-type enzymes have actually been functionally characterized.
Instant independent claims encompass:
an enormously vast genus of about 1x10^21 structurally undisclosed crRNA sequences;
an enormously vast genus of 1x10^60 structurally undisclosed gRNA DNA-target sequences;
an enormously vast genus of 1x10^60 structurally undisclosed gRNA Cas protein-binding sequences; and
an enormously vast genus of biologically different (target) bacterial species (pgs 84-113, Table 1).
Applicant argues that as of 2018, the use of CRISPR/Cas systems was part of the common general knowledge of the ordinary artisans.
Applicant’s argument(s) has been fully considered, but is not persuasive. The claims literally recite CRISPR/Cas systems at a high level of generality for which the application fails to provide adequate written description for the claimed genus.
Applicant argues that the disclosure provides a representative number of species so that one of skill in the art can visualize or recognize the members of the genus.
Applicant’s argument(s) has been fully considered, but is not persuasive.
While the specification discloses a genus of Cas nucleases molecules [0064], including, but not limited to, Type I Cas, Type II Cas, Type III Cas, Type IV Cas, Type V Cas, Cas 3, Cas9, Cpf, CasX, and CasY nucleases, see also Claims 125, 127, instant independent claims are vastly broader in scope, encompassing an essentially infinite genus of structurally and functionally undisclosed Cas-type nuclease variants, for which the art (Terns et al) taught that not all of the multitude of different Cas-type enzymes have actually been functionally characterized.
Instant independent claims encompass:
an enormously vast genus of about 1x10^21 structurally undisclosed crRNA sequences;
an enormously vast genus of 1x10^60 structurally undisclosed gRNA DNA-target sequences;
an enormously vast genus of 1x10^60 structurally undisclosed gRNA Cas protein-binding sequences; and
an enormously vast genus of biologically different (target) bacterial species (pgs 84-113, Table 1).
The art (Doudna et al) taught that such artificial sequences may share very little (roughly 50% identity) with naturally-occurring tracrRNAs and crRNAs.
At best, the specification discloses a prophetic example of a CRISPR/Cas3 system to target E. coli Nissle strain (e.g. [0099]).
2. Claims 120, 124-125, and 128-138 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 written description rejection.
The Examiner suggests cancellation of the phrases:
“wherein the crRNA or gRNA is operable with a Cas in a target bacterial cell” (Claims 123 and 139);
“wherein the crRNA or gRNA guides the Cas to a target nucleic acid sequence in the target bacterial cell to modify the target nucleic acid sequence” (Claim 123);
“the engineered nucleic acid encodes a Cas that is operable in a target bacterial cell to
modify a target nucleic acid sequence comprised by the target bacterial cell” (Claim 126); and
“operable in a target bacterial cell to modify a target nucleic acid sequence comprised by the target bacterial cell”.
Response to Arguments
Applicant argues that the specification provides workflows and procedural guidance.
Applicant’s argument(s) has been fully considered, but is not persuasive.
“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 argues that there is no undue experimentation.
Applicant’s argument(s) has been fully considered, but is not persuasive.
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 claims encompass:
an enormously vast genus of about 1x10^21 structurally undisclosed crRNA sequences;
an enormously vast genus of 1x10^60 structurally undisclosed gRNA DNA-target sequences;
an enormously vast genus of 1x10^60 structurally undisclosed gRNA Cas protein-binding sequences;
an essentially infinite genus of structurally and functionally undisclosed Cas-type nuclease variants; and
an enormously vast genus of biologically different (target) bacterial species (pgs 84-113, Table 1).
“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 argues that Makarova et al (2020) provides a review of the CRISPR/Cas system.
Applicant’s argument(s) has been fully considered, but is not persuasive. Makarova et al is published after, not before, the effective filing date of the instantly claimed invention (November 29, 2017). It is a violation of the natural law of physics and temporal mechanics, as we understand it, to use knowledge of the future to inform the ordinary artisan of the past.
3. The prior rejection of Claims 120 and 124-138 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of Applicant’s cancellation of “high copy number” in the independent claims.
4. Claims 120, 124-125, and 128-138 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 limitation “means for propagating the engineered nucleic acid at a high copy number”, recited in amended independent Claims 120 and 137, invokes 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. However, the written description fails to disclose the corresponding structure, material, or acts for performing the entire claimed function and to clearly link the structure, material, or acts to the function.
As discussed in the prior Office Action, at best, the specification discloses an engineered pUC19 shuttle vector plasmid (e.g. [0099]). However, instant claims are broader in scope than the pUC19 plasmid.
Therefore, the claim is indefinite and is rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph.
Applicant may:
(a) Amend the claim so that the claim limitation will no longer be interpreted as a limitation under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph;
(b) Amend the written description of the specification such that it expressly recites what structure, material, or acts perform the entire claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(c) Amend the written description of the specification such that it clearly links the structure, material, or acts disclosed therein to the function recited in the claim, without introducing any new matter (35 U.S.C. 132(a)).
If applicant is of the opinion that the written description of the specification already implicitly or inherently discloses the corresponding structure, material, or acts and clearly links them to the function so that one of ordinary skill in the art would recognize what structure, material, or acts perform the claimed function, applicant should clarify the record by either:
(a) Amending the written description of the specification such that it expressly recites the corresponding structure, material, or acts for performing the claimed function and clearly links or associates the structure, material, or acts to the claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(b) Stating on the record what the corresponding structure, material, or acts, which are implicitly or inherently set forth in the written description of the specification, perform the claimed function. For more information, see 37 CFR 1.75(d) and MPEP §§ 608.01(o) and 2181.
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).
5. Claims 120, 124-125, and 128-138 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.
The Examiner incorporates herein the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejection.
Claim limitation “means for propagating the engineered nucleic acid at a high copy number”, recited in amended independent Claims 120 and 137, invokes 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. However, the written description fails to disclose the corresponding structure, material, or acts for performing the entire claimed function and to clearly link the structure, material, or acts to the function.
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).
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”).
Applicant argues support for the limitation is found in [0608], and pUC19 of [0620].
[0608] is silent to “means for propagating the engineered nucleic acid at a high copy number”.
[0609] requires the ordinary artisans to discover for themselves a high copy number vector. This does not satisfy written description requirements.
As discussed in the prior Office Action, at best, the specification discloses an engineered pUC19 shuttle vector plasmid (e.g. [0099, 620]). However, instant claims are broader in scope than the pUC19 plasmid.
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.
The Examiner suggests amending the independent claims to recite “wherein the engineered nucleic acid is comprised by a pUC19 plasmid”.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
6. Claims 120, 124-125, 128-129, and 132-138 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Cronan et al (2013; of record in IDS), Wycuff et al (2000; of record), Cepham Life Sciences Research Products (November 6, 2024; of record), Kunin et al (WO 10/075424; of record in IDS), Zheng et al (Efficient genome editing in plants using a CRISPR/Cas system, Cell Research 23: 1229-1232, 2013; of record in IDS), and Agilent (pBluescript II Phagemid Vectors, Instruction Manual, 2021; of record in IDS).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Claim interpretation: independent Claims 120 and 137 recite the limitation “a nucleic acid encoding an antibacterial agent”, and the claims later recite “a nucleic acid encoding a guided nuclease system”. While the claims do not explicitly state the guided nuclease system is the antibacterial agent, the specification discloses (e.g. pg 14, item 34; pg 15, item 36; pg 20, item 65) “the antibacterial means comprises one or more components of a CRISPR/Cas system”. Thus, teachings of a CRISPR/Cas system is considered to fulfill the “antibacterial agent”.
With respect to Claims 120 and 137, Cronan et al is considered relevant prior art for having taught an in vivo method of packaging an engineered nucleic acid into a non-self-replicating transduction particle, the method comprising the step(s) of:
i) providing a bacterial host cell comprising the genome of a first phage (syn. prophage) encoding the capsid proteins of a first phage, wherein the prophage genome is a cos-type phage and is devoid of a functional packaging signal for packaging the first phage (e.g. pg 82, col. 1, Methods, 2.1 Construction of cos-deleted prophages; pg 83, col. 1, 3.1 Construction of cos-deleted lysogens; e.g. strains CY2113, CY2115, CY2116, CY2119, CY2120);
ii) introducing into the bacterial host cell an engineered nucleic acid molecule comprising an origin of replication and a cos packaging signal that is operable with the first phage (e.g. pg 84, col. 2, cosmid pCY9158B); and
iii) allowing the bacterial host cell to express the first phage capsid proteins, thereby packaging the engineered nucleic acid into the non-self-replicative transduction particles.
Cronan et al taught the cosmid is a derivative of the pTara plasmid of Wycuff et al, modified to further comprise the cos packaging signal (e.g. pg 84, col. 2, 3.2 Cosmid packaging by strain CY2120), whereby Wycuff et al illustrate the structural components of the pTara vector (Figure 1), for which there are no encoded phage structural protein genes for replication or packaging.
Thus, the ordinary artisan would have immediately understood the in vivo packaged cosmid of Cronan et al is a non-self-replicative transduction particle.
With respect to Claims 120 and 138, Cronan et al taught the cosmid is a derivative of the pTara plasmid of Wycuff et al, modified to further comprise the cos packaging signal (e.g. pg 84, col. 2, 3.2 Cosmid packaging by strain CY2120), whereby Wycuff et al illustrate the structural components of the pTara vector (Figure 1), for which there are no encoded phage structural protein genes for replication or packaging.
With respect to Claim 120, Cronan et al taught wherein the method further comprises the step of separating the particles from the bacterial host cells to obtain a plurality of the non-self-replicative transduction particles (e.g. pg 84, col. 2, 3.2 Cosmid packaging by strain CY2120; Table 2).
Cronan et al do not teach wherein the engineered nucleic acid encodes a crRNA (Claims 121-123, and 139) or a guide RNA (Claims 121-123, and 139), and a Cas nuclease (Claims 121-122, 124-127).
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim(s) 120, 124-125 and 137, Kunin et al is considered relevant prior art for having disclosed an engineered nucleic acid encoding a guided nuclease system, to wit, a CRISPR/Cas system comprising a CRISPR array (crRNA) and a Cas nuclease (e.g. pg 8, para 5; pg 16; pg 26, e.g. Cas3), wherein the engineered nucleic acid is a cosmid vector (pg 28, para 8).
Zheng et al is considered relevant prior art for having taught a minimal expression vector, pBluescript SK+ vector, comprising a replication origin and a promoter operably linked to a Cas9 cDNA and a promoter operably linked to gRNA (e.g. pg 19, Supplemental Materials, Vector construction; Figure S1a).
Those of ordinary skill in the pBluescript SK+ vector naturally comprises an origin of replication, a packaging signal of a first phage, and does not encode phage structural protein genes, as evidenced by Agilent (pBluescript II Phagemid Vectors, Instruction Manual, 2021; pg 3, Figure 1; pg 18, packaged by M13 helper phage).
pBluescript is an art-recognized high copy number plasmid, as evidenced below:
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To the extent Applicant argues otherwise, see the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, and 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description rejections.
Resolving the level of ordinary skill in the pertinent art.
People of the ordinary skill in the art will be highly educated individuals such as medical doctors, scientists, or engineers possessing advanced degrees, including M.D.'s and Ph.D.'s. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in molecular biology, cloning techniques, bacteriophage expression vectors, and gene-editing expression vectors. Therefore, the level of ordinary skill in this art is high.
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at ___, 82 USPQ2d at 1396.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute an artisan’s first transgene of interest, e.g. T7 RNA polymerase, as taught by Cronan et al, with a second transgene of interest, i.e. a CRISRP/Cas system, as taught/disclosed by Kunin et al and Zheng et al, in a cosmid expression vector capable of being packaged into non-self-replicative transduction particles with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute an artisan’s first transgene of interest, e.g. T7 RNA polymerase, with a second transgene of interest, i.e. a CRISRP/Cas system, in a cosmid expression vector capable of being packaged into non-self-replicative transduction particles because Kunin et al disclosed the CRISPR/Cas system may be expressed from cosmid expression vectors and delivered to target bacteria in the form of phage particles, and those of ordinary skill in the art had previously successfully reduced to practice the ability to clone and express a CRISPR/Cas system from a minimal expression vector capable of being packaged into bacteriophage capsid proteins (Zheng et al; Agilent), thereby producing non-self-replicative transducing particles (Cronan et al; Zheng et al; Agilent).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claims 120 and 138, Cronan et al taught the cosmid is a derivative of the pTara plasmid of Wycuff et al, modified to further comprise the cos packaging signal (e.g. pg 84, col. 2, 3.2 Cosmid packaging by strain CY2120), whereby Wycuff et al illustrate the structural components of the pTara vector (Figure 1), for which there are no encoded phage structural protein genes for replication or packaging.
With respect to Claim 120, Cronan et al taught wherein the method further comprises the step of separating the particles from the bacterial host cells to obtain a plurality of the non-self-replicative transduction particles (e.g. pg 84, col. 2, 3.2 Cosmid packaging by strain CY2120; Table 2).
With respect to Claim(s) 124-125, Kunin et al disclosed wherein the CRISPR/Cas system comprises a CRISPR array (crRNA) and a Cas nuclease (e.g. pg 8, para 5; pg 16; pg 26, e.g. Cas3).
Zheng et al taught wherein the CRISPR/Cas system comprises a guide RNA and a Cas9 nuclease.
With respect to Claims 132-133, Kunin et al disclosed wherein the CRISPR/Cas system is operably linked to either constitutive or inducible promoters (e.g. pg 28, para 5-6).
With respect to Claim 128, Cronan et al taught wherein the plurality of non-self-replicative transduction particles comprises as many as 1x10^12 particles (e.g. Table 2), which necessarily comprises at least 10^3 to 10^6 particles.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
With respect to Claim 135, Cronan et al taught wherein the engineered nucleic acid molecule comprising a cos packaging signal, which is a packaging signal endogenous to the first phage.
With respect to Claim 136, Cronan et al taught wherein the engineered nucleic acid is packaged in temperate phage (lambda lysogen) coat proteins.
With respect to Claim 134, Cronan et al taught wherein the non-self-replicative transduction particles were purified and suspended in lambda dilution buffer lacking gelatin (e.g. pg 82, col. 2, 2.2. Preparation and assay of phage particles). Cepham Life Sciences evidences that lambda dilution buffer comprises 50mM Tris-HCl, pH 7.5, 100mM NaCl, and 8mM MgSO4, and thus is considered to reasonably fulfill a pharmaceutical composition.
A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. The phrase "for administration to a human or animal for medical use" is an intended use limitation, which does not contain any further structural limitations with respect to claimed pharmaceutical composition comprising the non-self-replicative transduction particles suspended in lambda dilution buffer comprising 50mM Tris-HCl, pH 7.5, 100mM NaCl, and 8mM MgSO4, and lacking gelatin (see MPEP §2114).
With respect to Claim 129, Kunin et al disclosed wherein the target bacterial cell is, e.g. E. coli (pg 15).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Response to Arguments
Applicant argues that the pTara plasmid used by Cronan et al is a low copy number plasmid.
Applicant’s argument(s) has been fully considered, but is not persuasive. Applicant's arguments fail to comply with 37 CFR 1.111(b) because they amount to a general allegation that the claims define a patentable invention without specifically pointing out how the language of the claims patentably distinguishes them from the references. Applicant fail to provide objective evidence for the copy number of the pTara plasmid being a not high copy number and/or not moderate copy number. Applicant fail to provide objective evidence that the pTara plasmid is a low copy number plasmid.
Applicant argues that Cronan et al do not teach or suggest using a high copy number plasmid.
Applicant’s argument(s) has been fully considered, but is not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Cronan et al is considered relevant prior art for having taught an in vivo method of packaging an engineered nucleic acid into a non-self-replicating transduction particle, the method comprising the step(s) of:
i) providing a bacterial host cell comprising the genome of a first phage (syn. prophage) encoding the capsid proteins of a first phage, wherein the prophage genome is a cos-type phage and is devoid of a functional packaging signal for packaging the first phage (e.g. pg 82, col. 1, Methods, 2.1 Construction of cos-deleted prophages; pg 83, col. 1, 3.1 Construction of cos-deleted lysogens; e.g. strains CY2113, CY2115, CY2116, CY2119, CY2120);
ii) introducing into the bacterial host cell an engineered nucleic acid molecule comprising an origin of replication and a cos packaging signal that is operable with the first phage (e.g. pg 84, col. 2, cosmid pCY9158B); and
iii) allowing the bacterial host cell to express the first phage capsid proteins, thereby packaging the engineered nucleic acid into the non-self-replicative transduction particles.
Kunin et al is considered relevant prior art for having disclosed an engineered nucleic acid encoding a guided nuclease system, to wit, a CRISPR/Cas system comprising a CRISPR array (crRNA) and a Cas nuclease (e.g. pg 8, para 5; pg 16; pg 26, e.g. Cas3), wherein the engineered nucleic acid is a cosmid vector (pg 28, para 8).
Zheng et al is considered relevant prior art for having taught a minimal expression vector, pBluescript SK+ vector, comprising a replication origin and a promoter operably linked to a Cas9 cDNA and a promoter operably linked to gRNA (e.g. pg 19, Supplemental Materials, Vector construction; Figure S1a).
Those of ordinary skill in the pBluescript SK+ vector naturally comprises an origin of replication, a packaging signal of a first phage, and does not encode phage structural protein genes, as evidenced by Agilent (pBluescript II Phagemid Vectors, Instruction Manual, 2021; pg 3, Figure 1; pg 18, packaged by M13 helper phage).
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute an artisan’s first transgene of interest, e.g. T7 RNA polymerase, as taught by Cronan et al, with a second transgene of interest, i.e. a CRISRP/Cas system, as taught/disclosed by Kunin et al and Zheng et al, in a cosmid expression vector capable of being packaged into non-self-replicative transduction particles with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute an artisan’s first transgene of interest, e.g. T7 RNA polymerase, with a second transgene of interest, i.e. a CRISRP/Cas system, in a cosmid expression vector capable of being packaged into non-self-replicative transduction particles because Kunin et al disclosed the CRISPR/Cas system may be expressed from cosmid expression vectors and delivered to target bacteria in the form of phage particles, and those of ordinary skill in the art had previously successfully reduced to practice the ability to clone and express a CRISPR/Cas system from a minimal expression vector capable of being packaged into bacteriophage capsid proteins (Zheng et al; Agilent), thereby producing non-self-replicative transducing particles (Cronan et al; Zheng et al; Agilent).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
Applicant argues that the rejection is based upon the combination of six references.
Applicant’s argument(s) has been fully considered, but is not persuasive. In response to applicant's argument that the examiner has combined an excessive number of references, reliance on a large number of references in a rejection does not, without more, weigh against the obviousness of the claimed invention. See In re Gorman, 933 F.2d 982, 18 USPQ2d 1885 (Fed. Cir. 1991).
Applicant argues the secondary consideration of unexpected findings regarding the production of the claimed non-self replicative transduction particles to deliver CRISPR-guided vectors in E. coli host cells, thereby achieving a killing efficiency increase by about 2 logs when using a high copy number plasmid versus a low copy number plasmid.
Applicant’s argument(s) has been fully considered, but is not persuasive.
As a first matter, instant claims are directed to a method of producing non-self replicative transduction particles, not a method(s) of using said non-self replicative transduction particles.
As a second matter, the substantive issue is that those of ordinary skill in the art previously recognized and successfully reduced to practice the ability to clone and express the CRISPR/Cas9 system in, e.g. pBluescript SK+, expression vectors (Zheng et al).
Those of ordinary skill in the art previously recognized that pBluescript SK+ vector naturally comprises an origin of replication, a packaging signal of a first phage, and does not encode phage structural protein genes, thereby producing non-self replicative transduction particles when packaged by, e.g. M13 helper phage (Agilent).
Thus, it is considered no great surprise or unpredictable that the ordinary artisan could produce non-self replicative transduction particles encapsulating an expression vector encoding, e.g. a CRISPR/Cas9 system. Furthermore, given that recombinant bacteriophages is decades-old technology, having long-been routinely used in the art to deliver the artisan’s gene(s) of interest into target bacterial cells, e.g. E. coli host cells, it is also considered no great surprise or unpredictable that the ordinary artisan could use said non-self replicative transduction particles encapsulating an expression vector encoding, e.g. a CRISPR/Cas9 system, to deliver CRISPR-guided vectors into target bacterial cells, e.g. E. coli host cells.
Applicant argues that the Examiner has exercised impermissible hindsight.
Applicant’s argument(s) has been fully considered, but is not persuasive. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Kunin et al is considered relevant prior art for having disclosed an engineered nucleic acid encoding a guided nuclease system, to wit, a CRISPR/Cas system comprising a CRISPR array (crRNA) and a Cas nuclease (e.g. pg 8, para 5; pg 16; pg 26, e.g. Cas3), wherein the engineered nucleic acid is a cosmid vector (pg 28, para 8).
Zheng et al is considered relevant prior art for having taught a minimal expression vector, pBluescript SK+ vector, comprising a replication origin and a promoter operably linked to a Cas9 cDNA and a promoter operably linked to gRNA (e.g. pg 19, Supplemental Materials, Vector construction; Figure S1a).
Those of ordinary skill in the pBluescript SK+ vector naturally comprises an origin of replication, a packaging signal of a first phage, and does not encode phage structural protein genes, as evidenced by Agilent (pBluescript II Phagemid Vectors, Instruction Manual, 2021; pg 3, Figure 1; pg 18, packaged by M13 helper phage).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
Applicant argues that the combination of cited references do not teach or fairly suggest the instantly claimed invention, arguing the references individually.
Applicant’s argument(s) has been fully considered, but is not persuasive.
Applicant's arguments fail to comply with 37 CFR 1.111(b) because they amount to a general allegation that the claims define a patentable invention without specifically pointing out how the language of the claims patentably distinguishes them from the references.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant argues that Example 3 demonstrates the claimed system allows robust production of non-self replicative transduction particles encoding the guided nuclease system. Applicant also refers to Example 4.
Applicant’s argument(s) has been fully considered, but is not persuasive.
As a first matter, instant specification discloses only Example 1 and Example 2. There are no Example 3 or Example 4. Applicant instead appears to be referring to some other, presently unknown, document.
As a second matter, instant independent claims place no requirement onto the amount or purity of the thus-produced transduction particles. All that is required is that some plurality be produced. Cronan et al successfully demonstrated the ability to package the artisan’s engineered nucleic acid of interest into non-self replicative transduction particles. Both Kunin et al and Zheng et al taught the artisan’s engineered nucleic acid of interest to encode a CRISPR/Cas system, and transduction particles comprising said engineered nucleic acid of interest to encode a CRISPR/Cas system (Kunin et al), whereby those of ordinary skill in the art had long-recognized cosmids, including the pBluescript SK+ vector of Zheng et al, to be readily packaged into non-self replicative transduction particles.
7. Claims 130-131 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Cronan et al (2013; of record in IDS), Wycuff et al (2000; of record), and Cepham Life Sciences Research Products (2024; of record), Kunin et al (WO 10/075424; of record in IDS), Zheng et al (2013; of record in IDS), and Agilent (2021; of record in IDS), as applied to Claims 120, 124-129, and 132-138 above, and in further view of Ziermann et al (Characterization of the cos sites of bacteriophages P2 and P4, Gene 96: 9-15, 1990; of record in IDS).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Neither Cronan et al, Kunin et al, nor Zheng et al teach/disclose wherein the first cos-type phage is a P2 phage and the cos packaging signal is a P4 cos packaging signal.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim(s) 130-131, Ziermann et al is considered relevant prior art for having taught that P4 is a satellite bacteriophage that needs the capsid, tail, and lysis genes of a helper phage such as P2 (e.g. Introduction, col. 1). The cohesive ends of P4 and P2 are identical (syn. P4 cos site is operable with the P2 first phage). Ziermann et al taught the formation of transduction particles comprising cosmids comprising the P4 cos site (e.g. pg 11, col. 1) via in vivo packaging methods (e.g. pg 13, col. 1, “In vivo packaging of small cosmids into P4 sized heads”).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a first cos packaging site, e.g. a phage lambda cos site, as taught by Cronan et al, with a second cos packaging site, to wit, a P4 cos packaging site, as taught by Ziermann et al, in an in vivo method of producing non-self-replicating transduction particles comprising P2 capsid proteins with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute a first cos packaging site, e.g. a phage lambda cos site, with a second cos packaging site, to wit, a P4 cos packaging site, in an in vivo method of producing non-self-replicating transduction particles comprising P2 capsid proteins because those of ordinary skill in the art previously recognized that cosmid vector may be packaged using lambda cos packaging sites or P4 cos packaging sites, whereby P4 is a satellite bacteriophage that needs the capsid, tail, and lysis genes of a helper phage such as P2, and Ziermann et al successfully demonstrated he formation of transduction particles comprising cosmids comprising the P4 cos site via in vivo packaging methods.
It also would have been obvious to one of ordinary skill in the art to try a P4 cos packaging site with a reasonable expectation of success because “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipate success, it is likely that product not of innovation but of ordinary skill and common sense.” The ordinary artisan previously recognized that P4 is a satellite bacteriophage that needs the capsid, tail, and lysis genes of a helper phage such as P2, and Ziermann et al successfully demonstrated he formation of transduction particles comprising cosmids comprising the P4 cos site via in vivo packaging methods. The ordinary artisan could have pursued the known, finite number of predictable, potential options with a reasonable expectation of success.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Response to Arguments
Applicant argues that Ziermann et al do not cure the defect of Cronan et al, Wycuff et al, Kunin et al, Zheng et al, and Agilent.
Applicant’s argument(s) has been fully considered, but is not persuasive. The Examiner’s response to Applicant's argument(s) regarding Cronan et al, Wycuff et al, Kunin et al, Zheng et al, and Agilent are discussed above and incorporated herein. Applicant does not contest the teachings of Ziermann et al as applied to the obviousness to substitute a first cos packaging site, e.g. a phage lambda cos site, as taught by Cronan et al, with a second cos packaging site, to wit, a P4 cos packaging site, as taught by Ziermann et al, in an in vivo method of producing non-self-replicating transduction particles comprising P2 capsid proteins with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute a first cos packaging site, e.g. a phage lambda cos site, with a second cos packaging site, to wit, a P4 cos packaging site, in an in vivo method of producing non-self-replicating transduction particles comprising P2 capsid proteins because those of ordinary skill in the art previously recognized that cosmid vector may be packaged using lambda cos packaging sites or P4 cos packaging sites, whereby P4 is a satellite bacteriophage that needs the capsid, tail, and lysis genes of a helper phage such as P2, and Ziermann et al successfully demonstrated he formation of transduction particles comprising cosmids comprising the P4 cos site via in vivo packaging methods.
Applicant does not contest the teachings of Ziermann et al as applied to the obviousness to try a P4 cos packaging site with a reasonable expectation of success because “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipate success, it is likely that product not of innovation but of ordinary skill and common sense.” The ordinary artisan previously recognized that P4 is a satellite bacteriophage that needs the capsid, tail, and lysis genes of a helper phage such as P2, and Ziermann et al successfully demonstrated he formation of transduction particles comprising cosmids comprising the P4 cos site via in vivo packaging methods. The ordinary artisan could have pursued the known, finite number of predictable, potential options with a reasonable expectation of success.
Conclusion
8. No claims are allowed.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
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