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
Applicant’s election of Group I in the reply filed on 5/29/2026 is acknowledged.
The Applicant also elected the species, EF-1a polypeptide.
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)).
The requirement is deemed proper and is therefore made FINAL.
Claim Status
Claims 1-21 are pending.
Claims 8-21 are withdrawn from examination as being part of non-elected groups.
Claims 1-7 are being examined.
Claim Rejections - 35 USC § 112(a)
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.
Written Description
Claims 1-7 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 claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 recites “… or a sequence having at least 90% identity thereto or a functional fragment of said at least one Eimeria vaccine protein …”. Antigenic response against a protein antigen eliciting elevated serum antibody level depends on structural integrity of the protein as present in the native pathogen upon entry into (animal) host cells. The Applicant describes using EF-1a as an antigen to produce protective response against Eimeria (spec, p.27, line 25; p.29, line 3).
The Applicant does not describe any protein having less than 100% sequence identity to any of the Eimeria vaccine protein (antigen) including 450 amino acid long EF-1a (SEQ ID NO: 4) (spec, p.33, line 20-22). The Applicant also does not describe a functional fragment of said at least one Eimeria protein successfully used as an Eimeria vaccine protein.
Mutating up to 10% of the amino acid sequence along the entire length of an antigenic protein may change the structure of the protein (epitope) and how the exposed surface of the folded protein is presented in a host cell. Polypeptides with different amino acid sequences but the same biological function may/often fail to elicit the same antigenic response because the immune system recognizes specific molecular shapes or 3D structure (epitopes) rather than the overall function of the protein. Small structural variation(s) in a fragment of a protein can create completely different immunological profiles.
It is known in the art that mutating even a single crucial amino acid in a protein can change its 3D structure significantly and alters protein-protein interactions and immunogenicity. The Applicant does not describe any structure function relationship between the protein structure (i.e., its sequence) in terms of specific amino acid sequence(s) and/or domain(s)/motif(s) that must not be changed to maintain structural integrity as in the native protein in terms of acting as a vaccine antigen to provide protection against Eimeria.
Considering the breadth of the claims, lack of representative species of the broad genus claimed, lack of structure function relationship of the broad genus claimed, and unpredictability of the art, the Applicant does not appear to have been in possession of the claimed genus at the time this application was filed.
Scope of Enablement
Claims 1-7 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 the claimed method comprising Eimeria vaccine protein comprising the sequence set forth by SEQ ID NO: 4 and administering in chicken, does not reasonably provide enablement for a sequence having less than 100% identity to the Eimeria vaccine protein of SEQ ID NO: 4 or a functional fragment of said Eimeria vaccine protein and administering in any animals other than chicken. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Antigenic response against a protein antigen eliciting elevated serum antibody level depends on structural integrity of the protein as present in the native pathogen upon entry into the (animal) host cells. The Applicant describes an antigen, the EF-1a protein set forth by SEQ ID NO: 4 (GenBank XP_013234784) (spec, p.28, line 5), to produce protective response against Eimeria (spec, p.27, line 25; p.29, line 3).
The Applicant does not describe any protein having less than 100% sequence identity to any of the Eimeria vaccine protein, 450 amino acid long EF-1a, having the sequence of SEQ ID NO: 4. The Applicant defined the term "fragment" synonymous to "derivative" and "homologue" referring to a polypeptide which retains essentially the same biological function or activity as said polypeptide, that is, act as an antigen and/or provide treatment for and/or protection against disease (spec, p.7, line 26-29).
However, the Applicant also does not describe a functional fragment of the at least one Eimeria protein successfully used as an Eimeria vaccine protein.
A fragment of a native polypeptide and/or mutating up to 10% of the amino acid sequence along the entire length of an antigenic protein may change the structure of the protein epitope(s) and how the exposed surface of the folded protein is presented in a host cell. Polypeptides with different amino acid sequences but the same biological function may/often fail to elicit the same antigenic response because the immune system recognizes specific molecular shapes or 3D structure (epitopes) rather than the overall function of the protein. Small structural variation(s) in a fragment of a protein can create completely different immunological profiles.
The Applicant does not provide any guidance on how a skilled artisan would make a fragment and/or mutate an Eimeria vaccine protein protein having less than 100% sequence identity to any of the vaccine proteins (antigen) including 450 amino acid long EF-1a (SEQ ID NO: 4) while able to elicit the protective response against Eimeria. Producing a functional fragment or mutating up to 10% of the amino acid sequence anywhere along the entire length of an antigenic protein may change the structure of the protein epitope(s) in terms of how the exposed surface of the folded protein epitope is presented in a host cell. It is known in the art that mutating even a single crucial amino acid in a protein can change its 3D structure significantly and alters protein-protein interactions and immunogenicity.
Undue trial and error experimentations would be needed to make a fragment or mutate up to 10% of the amino acid residues of an Eimeria vaccine protein (antigen) including 450 amino acid long EF-1a (SEQ ID NO: 4) while maintaining the structural integrity as in the native protein in terms of acting as an antigen to provide protection against Eimeria.
The Applicant describes that coccidiosis caused by protozoan parasites of the genus Eimeria, is an infectious disease of poultry, swine, and cattle (spec, p.1, line 22-24). However, the Applicant only used (broiler) chickens to check the efficacy of the Eimeria vaccine (spec, p.35, line 28). The Applicant does not use swine or cattle or any animal other than chicken. Swine and cattle are obviously different from chickens, and results obtained with chickens is not predictive of how swine and cattle would respond. Undue experimentation would be required by one skilled in the art to determine an immunization regimen that would provide a protective response against Eimeria, using Eimeria vaccine antigen of SEQ ID NO: 4, for animals other than chicken.
Based on breadth of the claims, lack of any working example, lack of guidance in the instant description or in prior art, the specification at the time of the application filed would not have taught one skilled in the art how to make and use the full scope of the claimed invention without performing undue experiments.
Claim Rejections - 35 USC § 102(a)(1)
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 (i.e., changing from AIA to pre-AIA ) 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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zimmermann et al. (Antibody expressing pea seeds as fodder for prevention of gastrointestinal parasitic infections in chickens, 2009, BMC Biotechnology, 9:79).
Zimmermann et al. describes generating a panel of anti-Eimeria scFv (single chain) antibody fragments with high sporozoite-neutralizing activity (abstract, line 7-8). These antibodies were expressed either transiently in agrobacteria-infiltrated plant (tobacco) leaves or stably in plant (pea) seeds (as recited in claim 3) of transgenic pea plants (abstract, line 8-10), as recited in claims 1-2. Feeding (reads on to “orally administrating”) the plant product in an animal (chicken) demonstrated that oral delivery of flour prepared from the transgenic pea seeds had higher parasite neutralizing activity (abstract, line 12-14) leading to significant mitigation of infection caused by Eimeria (abstract, line 17-18). One of the transgenic pea plants expressing two most promising Eimeria vaccine proteins (scFv) in seeds show a yield of at least 10mg/kg (1.5-2 gm/kg of dry seeds) (p.12, right column, para 2, line 1-5), as recited in claim 1.
The scFv of Zimmerman et al. reads on “Eimeria vaccine antigen” of the instant claims, given the definition of “vaccine” by the Applicant (spec, p.23, line 26-29).
Claims 1-5 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sathisha et al. (Plant expressed Coccidial antigens as potential vaccine candidates in protecting chicken against Coccidiosis, 2012, Vaccine, 30: 4460– 4464).
Sathish et al. describes expressing two Eimeria vaccine proteins (EtMIC1 and/or EtMIC2) in a plant to protect animals (chicken) against Eimeria (p.4460, abstract). The yield of the purified protein was found to be more than 10mg/kg (25 mg/kg fresh biomass) (p.4462, left column, para 1, line 7-8), as recited in claims 1-3. The (oral) immunization schedule consisted of a primary dose adjuvanted with Freund’s complete adjuvant on 7 days old birds and two booster doses adjuvanted with Freund’s incomplete adjuvant on 14th and 21st days (p.4461, left column, para 9, line 7-10) which elicited more than 4 times serum antibody response than serum antibody response in an animal not administered said vaccine (p.4462, Fig. 2), as recited in claims 4-5.
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 (i.e., changing from AIA to pre-AIA ) 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, 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 for establishing a background for determining obviousness under 35 U.S.C. 103 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.
Claims 1-4 and 6-7 are rejected under 35 U.S.C. 103 as being unpatentable over Lillehoj et al. (US 10294483B2) in view of Zimmermann et al. and Jacobs et al. (Edible vaccines against veterinary parasitic diseases—Current status and future prospects, 2013, Vaccine, 31:1879– 1885).
Lillehoj et al. describes expressing recombinant Elongation Factor 1 alpha (EF-1α or EF-1a) protein (as recited in claim 6) from Eimeria tenella in E. coli (column 8, line 21; column 13, line 3-4) (reads on to “Eimeria vaccine protein” as recited in claim 1), to develop active immunity to, and control of, coccidiosis (abstract) as indicated by elevated serum (IgG) antibody response in the animals (column 14, line 19-24; Fig. 6A and 6B), as recited in claim 4. Lillehoj et al. teaches that the immunogenic composition comprising the recombinant EF-1a protein can be administered via ingestion (reads on to “orally administering”, as recited in claim 1) in an amount which is effective to protect the recipient poultry animals (column 10, line 57-61).
However, Lillehoj et al. does not describe expressing the Eimeria vaccine protein in a plant.
Zimmermann et al. describes feeding chickens with a composition comprising a plant product made from the transgenic plant seeds (as recited in claims 1-3) having a yield of at least 10 mg/kg (1.5-2 gm/kg of dry seeds) (as recited in claim 1) of the Eimeria vaccine protein (ScFv). Zimmermann et al. also describes that the Eimeria vaccine protein (and other antigenic proteins) expressed in seeds of transgenic feed provide a cost-effective production platform affordable for the animal health market (p.2, right column, para 1, line 2-5). The pea seeds demonstrate an excellent antibody (and other proteins) storage property as dry seeds could be stored at room temperature for long time periods without any loss of antibody/protein activity and can withstand elevated temperatures during the preparation of feed pellets (p.2, right column, line 2-9). Moreover, pea seed content protects Eimeria vaccine protein (and other proteins therein) from degradation in the GI tract and thus, feeding the chickens with fodder comprising the shred prepared from pea seeds expressing the desired antigenic/antibody protein(s) led to a protective and/or curative effect on infection of chickens with Eimeria parasite (p.2, right column, para 1, line 9-15).
Before the effective filing date of the invention, it would have been obvious to an ordinarily skilled artisan to express the Elongation Factor 1 alpha (EF-1α or EF-1a) protein from Eimeria tenella, as described by Lillehoj et al., in a plant including in pea and in pea seeds, as described by Zimmermann et al.
Before the effective filing date, an ordinarily skilled artisan would have been motivated to express the Eimeria vaccine protein, Elongation Factor 1 alpha (EF-1α or EF-1a) from Eimeria tenella, in a pea plant and seeds thereof. Plant expression system in a pea plant and seeds thereof offer excellent protein storage properties which include- i) dry seeds could be stored at room temperature for long time periods without any loss of protein activity, ii) can withstand elevated temperatures during the preparation of feed pellets, iii) pea seed content protects Eimeria vaccine protein (and other proteins therein) from degradation in the GI tract and thus, feeding the chickens with fodder comprising the shred prepared from pea seeds expressing the desired antigenic/antibody protein(s) led to a protective and/or curative effect on infection of chickens with Eimeria parasite, as described by Zimmermann et al. (p.2, right column, para 1, line 5-15).
Regarding claim 7, It is known in the art that targeting and retaining any heterologous recombinant (antigenic) protein to endoplasmic reticulum (ER) improve protein yield (Jacobs et al, p.1880, right column, para 3, line 14-17) which, is turn, would provide stronger antigenic response leading to enhanced serum antibody response.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Lillehoj et al. (US 10294483B2) in view of Zimmermann et al. and Jacobs et al. as applied to claims 1-4 and 6-7 above, and further in view of Sathisha et al. (Plant expressed Coccidial antigens as potential vaccine candidates in protecting chicken against Coccidiosis, 2012, Vaccine, 30: 4460– 4464).
Lillehoj et al. in view of Zimmermann et al. describe a method of producing a protective response to Eimeria in an animal by orally administering a composition comprising a plant (seed) product comprising at least one Eimeria vaccine protein (EF-1a) expressed at levels of at least 10mg/kg in seed and producing a protective response to said Eimeria resulting in elevated serum (IgG) antibody response in the animals, as discussed above.
Lillehoj et al. also describes that by using the ISA71 adjuvant (column 3, line 10-11; column 3, line 49; column 4, line 44-46) the serum antibody response against E. coli expressed Eimeria vaccine protein (EF-1a) is significantly increased (column 4, line 45) to about 2 times greater (Fig. 6A) than serum antibody response in an animal not administered said vaccine.
However, Lillehoj et al. in view of Zimmermann et al. do not describe a serum antibody response of at least 4 times greater than serum antibody response in an animal not administered said vaccine.
Sathish et al. describes expressing two Eimeria vaccine proteins (EtMIC1 and/or EtMIC2) in a plant to protect the animals (chicken) against Eimeria (p.4460, abstract). The yield of the purified protein was found to be more than 10mg/kg (25 mg/kg fresh biomass) (p.4462, left column, para 1, line 7-8). The (oral) immunization schedule consisted of a primary dose adjuvanted with Freund’s complete adjuvant on 7 days old birds and two booster doses adjuvanted with Freund’s incomplete adjuvant on 14th and 21st days (p.4461, left column, para 9, line 7-10) which elicited more than 4 times serum antibody response than serum antibody response in an animal not administered said vaccine (p.4462, Fig. 2), as recited in claims 4-5.
Before the effective filing date of the invention, it would have been obvious to an ordinarily skilled artisan to modify the method as described by Lillehoj et al. in view of Zimmermann et al., by replacing the adjuvant ISA71 with Freund’s complete adjuvant on 7 days old birds and two booster doses adjuvanted with Freund’s incomplete adjuvant on 14th and 21st days, as described by Sathish et al.
Before the effective filing date, an ordinarily skilled artisan would have been motivated to use Freund’s complete adjuvant on 7 days old birds and two booster doses adjuvanted with Freund’s incomplete adjuvant on 14th and 21st days while orally administering the Eimeria vaccine protein (EF-1a) expressed in plant seeds with a realistic objective to enhance serum antibody response further to at least 4 times greater, as described by Satish et al. (as compared to about 2 times greater, as described by Lillehoj et al.), which, in turn, would provide stronger protective response against Eimeria.
Conclusion
No claim is allowed.
Communication
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J.C.
/Jay Chatterjee/Examiner, Art Unit 1662
/BRATISLAV STANKOVIC/Supervisory Patent Examiner, Art Units 1661 & 1662
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