DETAILED ACTION
Election/Restrictions
Applicants’ election with traverse of Group I, claims 1, 2, 4 and 6-8, in the reply filed on 8/11/26 is acknowledged. The traversal is on the ground(s) that it would not place a serious burden on the Examiner to examine all of the claims. This has been fully and carefully considered but is not deemed persuasive. The inventions are independent or distinct, each from the other because: Inventions I and III are related as product and process of use. The inventions can be shown to be distinct if either or both of the following can be shown: (1) the process for using the product as claimed can be practiced with another materially different product or (2) the product as claimed can be used in a materially different process of using that product. See MPEP § 806.05(h). In the instant case, the proteins of Group I may be used for other purposes, such as in methods of detection. Inventions I and III are directed to an unrelated product and process. Product and process inventions are unrelated if it can be shown that the product cannot be used in, or made by, the process. See MPEP § 802.01 and § 806.06. The method of Group III does not use the polynucleotides of Group II and these are unrelated inventions. There would be a serious search and examination burden if restriction were not required because one or more of the following reasons apply: (a) the inventions have acquired a separate status in the art in view of their different classification; (b) the inventions have acquired a separate status in the art due to their recognized divergent subject matter; (c) the inventions require a different field of search (for example, searching different classes/subclasses or electronic resources, or employing different search queries); (d) the prior art applicable to one invention would not likely be applicable to another invention; (e) the inventions are likely to raise different non-prior art issues under 35 U.S.C. 101 and/or 35 U.S.C. 112, first paragraph.
The requirement is still deemed proper and is therefore made FINAL.
Claims 10-12, 14, 19-21 and 23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention.
Claims 1, 2, 4 and 6-8 are currently under examination.
Claim Rejections - 35 USC § 112-2nd paragraph
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 7 and 8 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.
Claims 1, 7 and 8 are vague and indefinite because it the mere recitation of a name, i.e., non-toxic domain of alpha toxin (ATX) protein, ntATX-D1 or ntATX-D2, to describe the invention is not sufficient to satisfy the Statute's requirement of adequately describing and setting forth the inventive concept. It is noted that the name “alpha toxin” is made by Staphylococcus aureus and varies species of Clostridium. The term “NtATX” is also used for and antioxidant gene from Nicotiana tabacum and ATX is also a compound produced by fungi, e.g., altertoxin. Therefore, the claim should provide any structural properties, such as the amino acid sequence of the protein/polypeptides, which would allow one to identify the protein without ambiguity. The mere recitation of a name does not adequately define the claimed protein. Claim 7 is also vague and indefinite because it is unclear what structure is encompassed by any ‘additional toxins or fragments thereof’ as this description is not enough to ascertain the structures in the vaccine for patent protection. Appropriate clarification and/or correction is required.
Claim Rejections - 35 USC § 112-Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 2, 4 and 6-8 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 instant claims recite, for example:
A vaccine composition comprising a non-toxic domain of an alpha toxin (ATX) protein and a pharmaceutically acceptable carrier, wherein the non-toxic domain comprises ntATX-D1 or ntATX-D2, or a combination thereof; or wherein the ntATX-D1 comprises at least 80% identity to SEQ ID NO: 2, or the ntATX-D2 comprises at least 80% identity to SEQ ID NO: 4; or wherein the vaccine may comprise any additional toxin or fragments thereof.
To fulfill the written description requirements set forth under 35 USC § 112, first paragraph, the specification must describe at least a substantial number of the members of the claimed genus, or alternatively describe a representative member of the claimed genus, which shares a particularly defining feature common to at least a substantial number of the members of the claimed genus, which would enable the skilled artisan to immediately recognize and distinguish its members from others, so as to reasonably convey to the skilled artisan that Applicant has possession the claimed invention. Applicants have not described the genus of claimed nicotinamide nucleotide transhydrogenase proteins/genes such that the specification might reasonably convey to the skilled artisan that Applicants had possession of the claimed invention at the time the application was filed. Even with the designation of “80% identical to SEQ ID NOs: 2 or 4” in the dependent claims, the written description is inadequate to support this breadth. With the written description of a genus, merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus. See Ariad, 598 F.3d at 1353 (The written description requirement guards against claims that "merely recite a description of the problem to be solved while claiming all solutions to it and . . . cover any compound later actually invented and determined to fall within the claim's functional boundaries."). Abbvie Deutschland GmbH & Co. v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 U.S.P.Q.2d 1780, 1790, 2014 BL 183329, 12 (Fed. Cir. 2014).
To fulfill the written description requirements set forth under 35 USC § 112, first paragraph, the specification must describe at least a substantial number of the members of the claimed genus, or alternatively describe a representative member of the claimed genus, which shares a particularly defining feature common to at least a substantial number of the members of the claimed genus, which would enable the skilled artisan to immediately recognize and distinguish its members from others, so as to reasonably convey to the skilled artisan that Applicant has possession the claimed invention. Applicants have not described the genus of claimed vaccines such that the specification might reasonably convey to the skilled artisan that Applicants had possession of the claimed invention at the time the application was filed.
The purpose of the "written description" requirement is broader than tomerely explain how to "make and use"; the applicant must convey with reasonableclarity to those skilled in the art that, as of the filing date sought, he or she was inpossession of the invention. The invention is, for purposes of the "writtendescription" inquiry, whatever is now claimed. See Vas-Cath, Inc. v. Mahurkar,935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).Furthermore, the written description provision of 35 USC § 112 is severable fromits enablement provision; and adequate written description requires more than amere statement that it is part of the invention and reference to a potential methodfor isolating it. The nucleic acid itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing the invention was 'ready for patenting' such as by disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. Moreover, because the claims encompass a genus of variant species, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was "ready for patenting" by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus'" (Id. at 1106); accordingly, it follows that an adequate written description of a genus cannot be achieved in the absence of a disclosure of at least one species within the genus.
It is noted that MPEP 2111.01 states that "[d]uring examination, the claims must be interpreted as broadly as their terms reasonably allow." The Court of Appeals for the Federal Circuit has recently held that a "written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." University of California v. Eli Lilly and Co., 1997 U.S. App. LEXIS 18221, at *23, quoting Fires v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993). To fully describe a genus of genetic material, which is a chemical compound, applicants must (1) fully describe at least one species of the claimed genus sufficient to represent said genus whereby a skilled artisan, in view of the prior art, could predict the structure of other species encompassed by the claimed genus and (2) identify the common characteristics of the claimed molecules, e.g., structure, physical and/or chemical characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or a combination of these (paraphrased from Enzo Biochemical).
University of Rochester v. G.D. Searle & Co. (69 USPQ2d 1886 (2004)) specifically points to the applicability of both Lilly and Enzo Biochemical to methods of using products, wherein said products lack adequate written description. While in University of Rochester v. G.D. Searle & Co. the methods were held to lack written description because not a single example of the product used in the claimed methods was described, the same analysis applies wherein the product, used in the claimed methods, must have adequate written description (see Enzo paraphrased above).
In the instant case, there is no structure associated with function with regard to the members of a genus of non-toxic alpha toxin proteins and their domains, from any source and with the added functional limitation of acting as a “vaccine”. Further, there is no written description for variants of these proteins with least 80% identical to the amino acid sequence of SEQ ID NO: 2 or 4.
The specification does not describe the structure for a representative number of genes from the Genus, with the required functionality in the claim. An argument can be made that the recited genus of polypeptides is adequately described by the disclosure of the structure of ntATX-D1 of SEQ ID NO: 2 or 30, or ntATX-D2 of SEQ ID NO: 4 and one could use structural homology to isolate those polypeptides with the required percent identity. However, as described below, the art clearly teaches the "Practical Limits of Function Prediction" Devos et al., (Proteins: Structure, Function and Genetics, 2000, Vol. 41: 98-107), teach that the results obtained by analyzing a significant number of true sequence similarities, derived directly from structural alignments, point to the complexity of function prediction. Different aspects of protein function, including (i) enzymatic function classification, (ii) functional annotations in the form of key words, (iii) classes of cellular function, and conservation of binding sites can only be reliably transferred between similar sequences to a modest degree. The reason for this difficulty is a combination of the unavoidable database inaccuracies and plasticity of proteins (Abstract, page 98) and the analysis poses interesting questions about the reliability of current function prediction exercises and the intrinsic limitation of protein function prediction (Column 1, paragraph 3, page 99) and conclude that "Despite widespread use of database searching techniques followed by function inference as standard procedures in Bioinformatics, the results presented here illustrate that transfer of function between similar sequences involves more difficulties than commonly believed. Our data show that even true pair-wise sequence relations, identified by their structural similarity, correspond in many cases to different functions (column 2, paragraph 2, and page 105).
Whisstock et al., (Quarterly Reviews of Biophysics 2003, Vol. 36 (3): 307-340,) also highlight the difficulties associated with "Prediction of protein function from protein sequence and structure": "To reason from sequence and structure to function is to step onto much shakier ground", closely related proteins can change function, either through divergence to a related function or by recruitment for a very different function, in such cases, assignment of function on the basis of homology, in the absence of direct experimental evidence, will give the wrong answer (page 309, paragraph 4), it is difficult to state criteria for successful prediction of function, since function is in principle a fuzzy concept. Given three sequences, it is possible to decide which of the three possible pairs is most closely related. Given three structures, methods are also available to measure and compare similarity of the pairs. However, in many cases, given three protein functions, it would be more difficult to choose the pair with most similar function, although it is possible to define metrics for quantitative comparisons of different protein sequences and structures, this is more difficult for proteins of different functions (page 312, paragraph 5), in families of closely related proteins, mutations usually conserve function but modulate specificity i.e., mutations tend to leave the backbone conformation of the pocket unchanged but to affect the shape and charge of its lining, altering specificity (page 313, paragraph 4), although the hope is that highly similar proteins will share similar functions, substitutions of a single, critically placed amino acid in an active-site residue may be sufficient to alter a protein's role fundamentally (page 323, paragraph 1). C. This finding is reinforced in the following scientific teachings for specific proteins in the art that suggest, even highly structurally homologous polypeptides do not necessarily share the same function and many functionally similar proteins will have little or no structural homology to disclosed proteins. For example, proteins having similar structure have different activities (structure does not always correlate to function); Witowski et al., (Biochemistry 38:11643-11650, 1999) teaches that one conservative amino acid substitution transforms a beta -ketoacyl synthase into a malonyl decarboxylase and completely eliminates beta-ketoacyl synthase activity. The art also teaches that functionally similar molecules have different structures; Kisselev L., (Structure, 2002, Vol. 10: 8-9) teach that polypeptide release factors in prokaryotes and eukaryotes have same function but different structures.
Because the art is unpredictable and the scope of the claim includes numerous structural variants and the genus is highly variant because a significant number of structural differences between genus members is permitted. The specification does not describe any members of the claimed genus by complete structure. One of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus, and thus, that the applicant was not in possession of the claimed genus. The claimed subject matter is not supported by an adequate written description because a representative number of species has not been described.
There are no drawings or structural formulas disclosed of any of thesefragments or variants of the claimed polypeptides. There is no teaching in thespecification regarding which 20% of the structure can be varied and still produce a polypeptide which has the function of acting as a vaccine. Although the disclosure of SEQ ID NOs: 2 and 4 combined with the knowledge in the art, may put one in possession of peptides that are at least 80% identical to SEQ ID NOs: 2 and 4, the level of skill and knowledge in the art is such that one of ordinary skill would not be able to identify without further testing which of those peptides would have the required functional activities. Based on the lack of knowledge and predictability in the art, those of ordinary skill in the art would not conclude that the applicant was in possession of the claimed genus of vaccines comprising an ntATX protein.
The claimed genera have widely variable structures and associated functions. As is discussed above, a minor change in structure may result in changes affecting function, since, the specification provided no additional information (species/variant/mutant) correlating structure with function, one skilled in the art cannot reasonably conclude that applicant had possession of the claimed invention at the time the instant application was filed.
Furthermore, "Possession may not be shown by merely describing how to obtain possession of members of the claimed ,genus or how to identify their common structural features" (See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895). A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the .gene does (function), rather what it is (structure), see University of California v. Eli Lilly & Co., 43 USPQ2d 1938, thus above claims lack adequate written description.
Applicant is referred to the revised guidelines concerning compliance with the written description requirement of U.S.C. 112, first paragraph, published in the Official Gazette and also available at www.uspto.gov
Claim Rejections - 35 USC § 112-Scope of Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 2, 4 and 6-8 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 vaccine composition comprising a non-toxic domain of an alpha toxin (ATC) protein and a pharmaceutically acceptable carrier, wherein the non-toxic domain comprises non-toxic ATX-D1 which comprises the amino acid sequence set forth in SEQ ID NO: 2, non-toxic ATX-D2 which comprises the amino acid sequence set forth in SEQ ID NO: 4, or a combination thereof,
does not reasonably provide enablement for:
A vaccine composition comprising a non-toxic domain of an alpha toxin (ATX) protein and a pharmaceutically acceptable carrier, wherein the non-toxic domain comprises ntATX-D1 or ntATX-D2, or a combination thereof; or wherein the ntATX-D1 comprises at least 80% identity to SEQ ID NO: 2, or the ntATX-D2 comprises at least 80% identity to SEQ ID NO: 4; or wherein the vaccine may comprise any additional toxin or fragments thereof.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Additionally, the specification only provides working examples with vaccine comprising the full-length domains of ntATX-D1 (SEQ ID NO:2) AND ntATX-D2 (SEQ ID NO: 4). The instant specification shows that (1) Immunization of turkeys against Clostridial dermatitis (CD), using ATX as a target vaccine antigen, can effectively prevent mortality and reduce disease severity; (2) Of the two non-toxic antigenic domains of ATX, the ntATX-D2 (SEQ ID NO: 4) seems to offer the most efficacious vaccine antigen platform in achieving protective immunity against CD in turkeys; and (3) The immune mechanisms of immunization-driven protection may include an effective antibody response along with enhanced CD4+ and CD8+ T cell functions, which collectively can control infection-induced inflammation.
However, there are no examples of functional variants with at least 80% identity to SEQ ID Nos: 2 or 4, e.g., claims 2 and 4. There are also no examples of “at least one immunogenic epitope of SEQ ID NO: 2 or 4,” e.g., claim 6, which can provided results as a vaccine. The specification states that substitutions, additions, or deletions, may be made to the defined sequences; however, the specification provides no guidance as which amino acids may be changed without causing a detrimental effect to the enzyme and with the added enzymatic function requirement. It is unpredictable as to which amino acids could be removed and which could be added. While it is known that many amino acid substitutions are possible in any given protein, the position within the protein’s sequence where amino acid substitutions can be made with a reasonable expectation of success are limited. Other positions are critical to the protein’s structure/function relationship, e.g., such as various positions or regions directly involved in binding, catalysis in providing the correct three-dimensional spatial orientation of binding and catalytic sites. These regions can tolerate only very little or no substitutions. Selective point mutation to one key residue could eliminate the function of the polypeptide. It could eliminate its functional properties. If the range of decreased binding ability after single point mutation of a protein antigen varies, one could expect point mutations in the protein antigen to cause varying degrees of loss of protection/function, depending on the relative importance to the binding interaction of the altered residue. Alternatively, the combined effects of multiple changes, as instantly claimed, in an antigenic determinant could again result in loss of function. A protein having multiple point mutations, or accumulated point mutations at key residues could create a new antigen that is precipitously or progressively unrecognizable. As stated above, Applicants have not shown the particular substitution and the result it produces. Applicants have provided no guidance to enable one of ordinary skill in the art how to determine, without undue experimentation, the effects of different amino substitutions and the nature and extent of the changes that can be made. It is expensive and time consuming to make amino acid substitutions at more than one position, in a particular region of the protein, in view of the many fold possibilities for change in structure and the uncertainty as to what utility will be possessed. See Mikayama et al. (Nov.1993. Proc.Natl.Acad.Sci. USA, vol. 90 : 10056-10060) which teaches that the three-dimensional structure of molecules is important for their biological function and even a single amino acid difference may account for markedly different biological activities. Rudinger et al. (June 1976. Peptide Hormones. Biol.Council. pages 5-7) also teaches that amino acids owe their ‘significance’ to their inclusion in a pattern which is directly involved in recognition by, and binding to, the receptor and the significance of the particular amino acids and sequences for different amino acids cannot be predicted a priori, but must be determined from case to case by painstaking experimental study. The instant claims allow for substitutions with amino acids of vastly different properties and they do not recite the specific changes in the claims.
Additionally, the specification provides no working examples of multivalent vaccines comprising any other toxins from an any source or fragments thereof (claim 7). It is well known in the prior art that combination/multivalent vaccines are highly unpredictable. Reduced immunogenicity can occur when multiple antigens are delivered as mixtures on the same or similar carrier proteins. In the latter situation, the immune system can become overloaded, resulting in an impaired response to any vaccine component. The combination of several different antigens into a single multivalent dose may result in competition among the different components and adversely affect the immunogenicity of any individual component. The instant specification has not provided results with any of the multitude of combination vaccines recited in instant claim 7. Given the inherent unpredictability of combination vaccines combined with the very large and divergent group of antigens recited in claim 7, it would take one skilled in the art undue experimentation to make and/or use the invention.
Genentech Inc. v. Novo Nordisk A/S (CAFC) 42 USPQ2d 1001 clearly states: “Patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable. See Brenner v. Manson, 383 U.S. 519, 536, 148 USPQ 689, 696 (1966) (stating, in context of the utility requirement, that "a patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion.") Tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.”
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 2, 4 and 6 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter because the claims are drawn to a protein which exists in nature. The claimed polypeptides are not markedly different from what naturally exists in nature because the use of the open language “comprising” includes the scope of the full-length, naturally occurring alpha-toxin. Even though isolation structurally changes a protein from its natural state, the resultant difference is no enough to render the isolated protein markedly different because the genetic structure and the amino acid sequence has not been altered. The use of the term “vaccine” is an intended use only. There is no structural difference between the claimed invention and the naturally-occurring alpha toxin which would inherently comprise both non-toxic domains. See Myriad, 133 S.Ct. at 2166-18.
Claim Rejections - 35 USC § 102
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.
Claim(s) 1, 4, 6 and 8 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Tweten et al (US Patent No. 7,179,888 which corresponds to WO 2003/005957 Jan. 2003).
Tweten et al disclose a claimed vaccine which comprises a C. septicum alpha toxin which is 100% identical to Applicant’s SEQ ID NO:4. The invention comprises a variety of C. septicum alpha toxin derivatives (mutants) which are deficient in at least one specific function required for toxicity such that they are useful as vaccines for both humans and animals, e.g., non-toxic vaccines. It is used to protect against infections caused by C. septicum in animals or in humans, e.g. in colon cancer patients, diabetics, leukemia patients and neutropenics. Additionally, a serum comprising antibodies raised against an alpha toxin mutant can be used to confer passive immunity. Antibodies to an alpha toxin mutant may be used in diagnostic tests or in treatments to clear alpha toxin from bodily fluids. The mutant alpha toxins can be produced by recombinant methods.
Tweten teaches that adjuvants may be included in the vaccine to enhance the immune response in the subject. Such adjuvants include, for example, aluminum hydroxide, aluminum phosphate, Freund's Incomplete Adjuvant (FCA), liposomes, ISCOM, and the like. The vaccine may also include additives such as buffers and preservatives to maintain isotonicity, physiological pH and stability. Parenteral and intravenous formulations of the vaccine may include an emulsifying and/or suspending agent, together with pharmaceutically-acceptable diluents to control the delivery and the dose amount of the vaccine. Given the use of the open language “comprising” Tweten’s toxin vaccine anticipates the claims.
Claim(s) 1, 2, 4, 6 and 8 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Buckley et al (US Publication No. US20060159687A1).
Buckley teaches an alpha toxin comprising SEQ ID NO: 8 which is 100% identical to Applicants’ SEQ ID NO: 4 and 100% identical to Applicants’ SEQ ID NO: 2. Paragraph [0006] In one example, a modified aerolysin molecule includes a lung cancer specific binding agent, such as AFAI. In some examples, a modified aerolysin molecule includes an aerolysin homolog, such as Clostridium septicum alpha toxin, and a lung cancer specific binding agent, such as AFAI. Pharmaceutical compositions that include the disclosed modified aerolysin molecules are also provided. Given the use of the open language “comprising” Buckley’s toxin anticipates the claims. The term “vaccine” is an intended use only. 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. If the prior art structure is capable of performing the intended use, then it meets the claim.
Claim(s) 1, 2, 4, 6 and 8 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by He et al (CN109111509 Jan. 1, 2019).
He et al teach a Clostridium septicum mutant C86L/S189C alpha toxin protein, SEQ ID NO: 3 which is 100% identical to Applicants’ SEQ ID NO: 4 and Clostridium septicum alpha toxin protein, SEQ ID NO: 1 which is 100% identical to Applicants’ SEQ ID NO: 2. He teaches that Clostridium septium alpha toxin mutant useful for e.g. preparing vaccine. It is taught that, preferably, the vaccine adjuvant comprises aluminum hydroxide glue, Freund's complete adjuvant, Freund's incomplete adjuvant, white oil adjuvant, MF 59 adjuvant, or Montanide ISA series adjuvant; preferably Montanide ISA series adjuvant is used; more preferably ISA 15A adjuvant is used.
Pertinent art, not presently relied upon:
Buckley, JT (US Patent No. 8916161) Seq 74 is 100% identical to Applicant’s SEQ ID NO: 4.
Du et al (CN108578686 Sep. 28, 2018) Clostridium perfringens alpha toxin protein SEQ: 6 which is 100% identical to Applicant’s SEQ ID NO: 4. Preparing sheep recombinant subunit vaccinating agent,
Buckley, JT (WO2007140618; Dec. 13, 2007) Clostridium septicum alpha toxin protein SEQ ID NO:4 which is 100% identical to SEQ ID NO: 4.
Buckley ET AL (WO 2004078097 Sept. 16, 2004) C. septicum alpha toxin, seq id 8 which is 100% identical to Applicants SEQ ID NO: 2.
Amimoto et al (Vet. Microbiol. 114:51-59(2006). Genetic variation and cross-reactivity of Clostridium septicum alpha-toxin 100% to seq 4 and 2.
Ballard et al (Infect. Immun. 63:340-344(1995) and Ballard FEMS Microbiol. Lett. 117:287-292(1994). The primary structure of Clostridium septicum alpha-toxin exhibits similarity with that of Aeromonas hydrophila aerolysin."; 100% to SEQ ID NO: 4 and 2
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jennifer E. Graser whose telephone number is (571) 272-0858. The examiner can normally be reached on Monday-Friday from 8:00 AM-4 PM.
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Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (571) 272-0500.
/JENNIFER E GRASER/ Primary Examiner, Art Unit 1645 9/15/26
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