DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Claims 67, 71-78 are pending.
Applicant’s election of Group II in the reply filed on 04/17/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Further, although there was a species election requirement, it appears that the claim amendments would moot the requirement. Thus, the species election requirement is withdrawn.
Priority
The claims benefit to provisional application 63/110,288 and 63/184,728, filed on 11/05/2020 and 05/05/2021, respectively, via its PCT filing of PCT/US2021/058123, filed on 11/4/2021, is recognized. All claims enjoy the benefit of ‘288’s filing date.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/11/2023 and 02/04/2026 were filed before the mailing date of this first Office Action. 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 are objected to because the designation of sequence motif in Fig. 1 is difficult to read; e.g. is the first sequence “ACR promoter” followed by “repeat” and “spacer 1;” the types of Cas represented by the sequence in Fig. 1F-1K, 1L-1Q are difficult to read also. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim 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.
Enablement:
Claims 67, 71-78 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.
It is apparent that the p1772e005 (claim 67), p1835e002 (claims 72 and 73), p1106e003 (claims 72-74), p2131e002(claims 72-74), p4430 (claims 75 and 76), and p1695 (claims 75 and 76) bacteriophages are required to practice the claimed invention. As such the biological material must be known and readily available or obtainable by a repeatable method set forth in the specification, or otherwise known and readily available to the public. If it is not so obtainable or available, the requires of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, may be satisfied by a deposit of the bacteriophages.
The process disclosed in the specification does not appear to be repeatable, it is not clear that the invention will work with commonly available material and it is not apparent if the biological materials considered necessary to make and use the invention is both known and readily available to the public. E.g., Fig. 3A provides a schematic representation of the genome of a wild type phage p1772 and its engineered variant, where a certain portion of phage genome was removed at ~10kb position and replaced with either CRISPR-Cas enzyme or an array and CRISPR-Cas enzyme. This applies to the engineered bacteriophages (phage p1772e005 deposited as ATCC Accession Number PTA-127029, phage p1835e002 deposited as ATCC Accession Number PTA-127026, phage p1106e003 deposited as ATCC Accession Number PTA-127023, phage p2131e002 deposited as ATCC Accession Number PTA-127037). First, a skilled artisan cannot make a sequence at least 80% identical to an undisclosed sequence for both wild-type and engineered bacteriophages. Second, the schematic representation lacks the details to repeat the method with exact precision to derive the p1772e005 phage; i.e. which exact positions and length or the particular sequence of the phage was removed.
It is noted that Applicants have deposited biological material but there is no indication in the specification as to public availability. Therefore, a deposit at a recognized depository may be made to obviate this rejection.
Although the ATCC# of the bacteriophages are provided (phage p1772e005 deposited as ATCC Accession Number PTA-127029, phage p1835e002 deposited as ATCC Accession Number PTA-127026, phage p1106e003 deposited as ATCC Accession Number PTA-127023, phage p2131e002 deposited as ATCC Accession Number PTA-127037, phage p4430 deposited as ATCC Number PTA-127047, and phage p1695 deposited as ATCC Accession Number PTA-127028, par. 93-95), a deposit does not always support enablement. The deposit also requires compliance with 37 CFR 1.801-1.809, which addresses procedural matters, including whether the deposit was made under the Budapest Treaty or as a non-Budapest Treaty Deposits (see MPEP 2409 and 37 CFR 1.807). Here, the record does not indicate whether it was deposited under Budapest or non-Budapest Treaty.
If the deposit is made under the terms of the Budapest Treaty, then a statement, affidavit or declaration by Applicants, or by an attorney of record over his or her signature and registration number, or by someone in a position to corroborate the facts of the deposit, that the instant invention will be irrevocably and without restriction released to the public upon the issuance of a patent, would satisfy the deposit requirement made herein.
If the deposit is a non-Budapest Treaty deposit, then in order to certify that the deposit meets the requirements set forth in 37 CFR 1.801-1.809 and MPEP 2402-2411.05, a statement, affidavit or declaration by Applicant or by an attorney of record over his or her signature and registration number, or by someone in a position to corroborate the facts of the deposit would satisfy the requirements herein by stating and providing that:
(a) During the pendency of the application, access to the invention will be afforded to the Commissioner upon request;
(b) All restrictions upon availability to the public will be irrevocably removed upon granting of the patent;
(c) The deposit will be maintained in a public depository for a period of 30 years, or 5 years after the last request or for the enforceable life of the patent, whichever is longer; and
(d) Provide evidence of the test of the viability of the biological material at the time of deposit (see 37 CFR 1.807).
Written Description:
Claims 67, 72-78 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 claimed invention encompasses “at least 80% sequence identity” to claimed engineered-variant or wild-type bacteriophage.
When claims 67, 72-76 are analyzed in light of the specification, instant invention encompasses any variant of the claimed bacteriophage that has 80% sequence identity with the claimed variant or wild-type phage and encompasses a variant/wild-type phage that does not have the CRISPR system introduced in the variant.
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. In the instant case, the specification engineered variants (e.g., p1772e005), which represents the 100% sequence identity, are the only species whose complete structure is disclosed. Since the specification does not disclose the complete sequences of the wild-type and variant bacteriophages, it is difficult to compare the sequence identity between the variants and the wild-type or between wild-types. E.g. p1772e005 (PTA-127209) comprises crArray 1 (SEQ ID NO: 83) and BBa_j23109 Cas promoter with PaIC casID (see pg. 128, Table 1A excerpt provided below):
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The PaIC (SEQ ID NO: 25, 6024 bp, see Fig. 1F-1K) comprises SEQ ID NO: 83 and SEQ ID NO: 2 (BBa_J23109 promoter, Table 1B, pg. 131). Thus if the variant p1772e005 is 100 kb, then a bacteriophage variant with at least 80% sequence identity encompasses (can have ~20 kb variance) variants not having the PaIC insert since it is only ~6 kb.
Thus, the genus encompasses a large number of variants and molecules that have a different structure, and the specification does not describe the complete structure of a representative number of species of the large genus of “at least 80% sequence identity” of claimed phages or functional equivalents thereof. Additionally, the specification does not describe the complete structure of the wild-type or variant phages, i.e. the inherent sequence is not disclosed.
Next, then, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics (i.e. other than nucleotide sequence), specific features and functional attributes that would distinguish different members of the claimed genus. In the instant case, the only other identifying characteristic is the identity of either the variant or wild-type phage and their ability to infect a target bacterium. Since the sequence, i.e. the structure, of the wild-type or variant phage is not disclosed, it is difficult to tie its inherent functional activity to a particular sequence/structure.
The inventions of dependent claims 77-78 require the use of the inventions of claim 67 and therefore are likewise rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement.
Applicant’s attention is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112(a) or Pre-AIA 35 U.S.C. 112, first paragraph, "Written Description" Requirement (MPEP2163).
In conclusion, Applicant’s disclosure of only the 100% sequence identity of variants/wild-type phages, the claimed broad genus is not deemed sufficient to reasonably convey to one skilled in the art that Applicant was in possession of the claimed broad genus at the time the application was filed. Thus, it is concluded that the written description requirement is not satisfied for the claimed genus.
Scope of Enablement:
Claims 67, 71-73, 77, 78 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 of killing a Pseudomonas aeruginosa in a subject in need thereof, the method comprising at least four different bacteriophages from the group of consisting of phage p1772e005 deposited as ATCC Accession Number PTA-127029, phage p1835e002 deposited as ATCC Accession Number PTA-127026, phage p1106e003 deposited as ATCC Accession Number PTA-127023, phage p2131e002 deposited as ATCC Accession Number PTA-127037, phage p4430 deposited as ATCC Number PTA-127047, and phage p1695 deposited as ATCC Accession Number PTA-127028 with at least one bacteriophage is phage p1772e005 deposited as ATCC Accession Number PTA-127029, the specification does not reasonably provide enablement for two claimed variant or wild-type bacteriophages to kill any Pseudomonas bacterium. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
When considering the scope of enablement, the Wands factors need to be reviewed, which poses whether the experimentation needed to practice the invention is undue or unreasonable. Determining undue experimentation requires analysis of, but not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In the instant case, the claimed invention is directed to a “method of killing a Pseudomonas bacterium in a subject in need thereof, the method comprising administering to the subject a composition comprising a first bacteriophage comprising at least 80% sequence identity with p1772e005 and at least a second bacteriophage.” The additional claims recite other engineered bacteriophages (p1835e002, p1106e003, and p2131e002) or wild-type bacteriophages (p4430 and p1695) that are added to the composition. Here, the claimed invention of engineered bacteriophage comprises introducing CRISPR system that express spacers complementary to a target nucleotide in a Pseudomonas species.
The breadth of the claims/nature of the invention: Under BRI, the claims encompass that the composition of cl. 67 would infect and kill any Pseudomonas bacterium.
The state of the prior art: The claims themselves raise the question if a composition of claim 67 kills any bacterium then the addition of a new bacteriophage is not required or has a redundant function. Regardless, it is known, as the specification points out that bacteria, including Pseudomonas bacterium, have achieved a level of antibiotic resistance or create physiological complications following infection (par. 185). Further, a bacteriophage is limited to a given bacterial strain and injecting their genetic material into an incompatible strain is counterproductive, while others like P1phage has been shown to inject DNA in a range of gam-negative bacteria (par. 83). Thus, the level of infectivity for a bacterium depends on the type of bacteriophage and thus there is uncertainty whether any bacteriophage will infect any bacterium.
The level of one of ordinary skill: The level of one of ordinary skill is high.
The level of predictability in the art: As noted above, the art of antibiotic resistance is unpredictable and that there has to be compatibility between the bacteriophage and bacterium for bacteriophage to insert its genetic material into a bacterium.
The amount of direction provided by the inventor/existence of working examples: Here, the specification clearly indicates which wild-type and engineered Samunavirus and engineered Pbunavirus infect and, consequently, kill species of P. aeruginosa (see Table 5A, pg. 156, for Pbunavirus and Table 5B, pg. 158, for Samunavirus). The “+” sign indicates “wherein the phage infects a target Pseudomonas,” (par. 4, pg. 3) while the “-“ designation would indicate that the phage does not infect.
E.g., examining Table 5B for Samunavirus p1772e005 and just the rows on pg. 158, of 15 variants of P. aeruginosa tested, the table indicates that only 3 were infected. Further, under BRI of claim 67, the second bacteriophage does not have to be different than the 1st bacteriophage. Thus, although a 100% is not required for enablement, here, 3 positive results out of 15 would not be interpreted as a reasonable likelihood of infection success. It is the mixture of multiple engineered bacteriophages along with wild-type bacteriophage that results in high percentage of numerous types (very close to 100%) of Pseudomonas infectivity (see Table 6A and 6B, where a cocktail of at least 4 engineered variants of bacteriophages results in increased number of type of Pseudomonas are infected). Table 6A, pg. 163, discloses a “ck000125” cocktail that comprises engineered Samunaviruses p1772e005 and p2131e002 and engineered Pbunaviruses p1106e003, p1835e002. Further, the specification highlights based on their results: “Overall, host range was increased in phage cocktail assays as shown by an increase in positive (+) hits listed on Table 6B, as compared to individual phage assays in Table 5A and Table 5B” (par. 356). The results of 6C are summarized in Table 6C, with the “CK000125” cocktail mix demonstrating ~90% of the hosts being infected regardless of the source of isolates (pg. 166). Thus a cocktail comprising at least 4 different phages has a more reasonable likelihood of success of killing any Pseudomonas bacterium.
Thus, a cocktail mixture is required as opposed to a single CRISPR engineered bacteriophage to effectively kill any Pseudomonas bacterium. Thus, there is unpredictability in the art in the ability to kill any Pseudomonas bacterium. The unpredictability is best illustrated by Table 6B, in which certain types of Pseudomonas have “-“ sign even following attempts to infect with various cocktail mix, including ck000125 (see gray highlighted portion below of Table 6B, pg. 164).
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The quantity of experimentation: Thus there is a requirement of undue or unreasonable amount of experimentation to identify, isolate and then transform the wild-type to engineered variant of the bacteriophage and then test to identify if the CRISPR variant infects, and consequently, kills a bacterium. Thus, cl. 67, 71-73, 77, 78 are rejected.
Allowable Subject Matter
No claim allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KEYUR A. VYAS whose telephone number is (571)272-0924. The examiner can normally be reached M-F 9am - 4 pm (EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jennifer Dunston can be reached at 571-272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KEYUR A VYAS/Examiner, Art Unit 1637
KEYUR VYAS
Examiner
Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
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