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 .
The preliminary amendment filed on 3/21/2024 is acknowledged. Claims 1-29 are cancelled. New claims 30-49 are pending and are currently under examination.
Information Disclosure Statement
The information disclosure statements filed on 3/21/2024 and 4/10/2025 have been considered. Signed copies are enclosed.
Claim Objections
Claims 31-33 are objected to because of the following informalities: the claims contain grammar errors. In particular, there is no article before the word “proportion”. Appropriate correction is required.
Claim 33 is objected to because of the following informalities: Each claim must begin with a capital letter and end with a period. See Fressola v.Manbeck, 36 USPQ2d 1211 (D.D.C. 1995). Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 30-49 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claim 30 is rendered indefinite by the phrase “composition which comprises 200ug of a C. difficile toxoid”. It is not clear if the total of both SEQ ID NO:84 and 86 is 200ug or if the claim requires 200ug of SEQ ID NO:84 and an unknown amount of 86.
Claim 30 is rendered indefinite by the phrase “wherein the immune response against C. difficile toxin B is greater than a protective threshold value when measured after the third administration.” It is not clear if the claim is simply stating the outcome of the method or if the step of measuring the immune response against toxin B after the third administration is required.
Claim 31 is rendered indefinite by the phrase “achieving toxin B-specific neutralizing antibody titers greater than the protective threshold value is at least 75%”. The parent claim requires achieving an immune response that is greater than a protective threshold value but there is nothing in the parent claim about achieving neutralizing antibody titers. It is not clear if the protective immune response in the parent is supposed to be a high enough neutralizing antibody titer. If this is not the immune response in the parent, then the limitation lacks antecedent basis. If it is the immune response recited by the parent, then the parent claim already requires 100% of the humans to achieve the protective threshold.
Claim 32 is rendered indefinite by the phrase “achieving toxin B-specific neutralizing antibody titers greater than the protective threshold value is at least 80%”. The parent claim requires achieving an immune response that is greater than a protective threshold value but there is nothing in the parent claim about achieving neutralizing antibody titers. It is not clear if the protective immune response in the parent is supposed to be a high enough neutralizing antibody titer. If this is not the immune response in the parent, then the limitation lacks antecedent basis. If it is the immune response recited by the parent, then the parent claim already requires 100% of the humans to achieve the protective threshold.
Claim 33 is rendered indefinite by the phrase “achieving toxin B-specific neutralizing antibody titers greater than the protective threshold value is at least 20, 30, 40 or 50% higher after receiving the third administration about 180 days after the first administration compared to receiving the third administration about 30 days after the first administration”. The parent claim requires achieving an immune response that is greater than a protective threshold value but there is nothing in the parent claim about achieving neutralizing antibody titers. It is not clear if the protective immune response in the parent is supposed to be a high enough neutralizing antibody titer. If this is not the immune response in the parent, then the limitation lacks antecedent basis. If it is the immune response recited by the parent, then the parent claim already requires 100% of the humans to achieve the protective threshold.
Claims 33 and 35-38 are indefinite because there is no part of the parent claim which requires a third administration 30 days after the first administration. It is not clear if the claims are simply stating the outcome of the method or if there is some step of the claims that are missing.
Claim 38 is rendered indefinite by the phrase “when measured about 7 days after the third administration.” It is not clear if the claim is simply stating the outcome of the method or if the step of measuring the immune response against toxin B after the third administration is required.
Claims 42 and 43 are rendered indefinite by the phrase “neutralizing monoclonal antibody.” The term “monoclonal” with reference to antibodies is properly used in reference to a population of antibodies. The term does not make sense in reference to a single antibody. Further, the population of antibodies produced in the body by a given B cell is always monoclonal. When an antigen is administered to a body in order to induce production of antibodies, it will necessarily induce a polyclonal population of antibodies. Each species of antibody is, by itself, a population of monoclonal antibodies. Thus, it is not clear what limitations are actually engendered by the way applicant is improperly using the term “monoclonal antibody” in the claims.
Claim 44 is rendered indefinite by the phrase “each having a purity of at least 90% or greater. It is not clear at what point in the method the toxoids should be at this purity or what the percentage is of. For example, applicant could be referring to the concentration of toxoid in water. In the final composition, there is likely to be an excipient of some sort. Would this count as an impurity (since it is not the toxoid)? Likewise, how does an adjuvant fit into the purity? Further, it is not clear how “or greater” could be possible when the purity is already “at least” 90%.
Claim 45 is rendered indefinite by the phrase “comprises a C. difficile toxoid A and/or a C. difficile toxoid B, in a ratio.” As the parent claim requires administration of both toxoid A and toxoid B, and as the instant claim requires a ratio of both, one cannot have a choice of toxoid A or toxoid B.
Claim 46 is rendered indefinite by the phrase “comprises a C. difficile toxoid A and/or a C. difficile toxoid B, in a ratio.” As the parent claim requires administration of both toxoid A and toxoid B, and as the instant claim requires a ratio of both, one cannot have a choice of toxoid A or toxoid B.
Claim 49 is indefinite because it is not clear at what point in the method the toxoids are to be lyophilized. Toxoids are generally administered as an injection. The examples in the specification are of injections. One would have to reconstitute a lyophilized composition prior to injecting. However, at the point of administration, the composition would no longer be lyophilized.
Claim Rejections - 35 USC § 103
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.
Claims 30-49 are rejected under 35 U.S.C. 103 as being unpatentable over Sheldon et al. (Vaccine, 34:2082-2091, 2016) as evidenced by ClinicalTrials.gov (https://clinicaltrials.glv/ct2/show/NCT01706367, accessed on 5/5/2022).
The instant claims are drawn to methods for eliciting an immune response in a human against C. difficile toxin A or toxin B, comprising administering a composition comprising 200ug or a toxoid comprising SEQ IUD NO:84 and a toxoid comprising SEQ ID NO:86, wherein the composition is administered at least 3 times and where the second administration is about 30 days after the first administration and the third is about 180 days after the first, and wherein the immune response against toxin B is greater than a protective threshold value when measured after the third administration.
The examples in the instant specification refer, on page 63, to the phase I trial B5091001. The specification states that the examples used SEQ ID NO:4 and 6, in equal amounts, inactivated by EDC and NHS were used as the vaccine. The clinicaltrials.gov webpage shows that trial B5091001 has the identifier NCT01706367 and that the associated publication is Sheldon et al. Sheldon et al also states that their work was the work of trial NCT01706367. Therefore, Sheldon et al used SEQ ID NO:4 and 6, inactivated by EDC and NHS as their vaccine. The disclosed SEQ ID NOs 4 and 6 comprise the instantly claimed SEQ ID NOs 84 and 86. A three-dose regimen, including 200ug of toxoid, administered at day 1, month 1, and month 6 was used (see abstract and section 2.2, page 2083). The toxoids were lyophilized prior to reconstitution and the vaccine included an aluminum adjuvant (see section 2.2, page 2083). It is noted that the claims have functional limitations which are the result of performing the method, rather than limitations on what the method is. If the method works as applicant claims, administration of the same product to the same population would necessarily result in the same outcome. Therefore, although the reference is silent with respect to the longevity of the immune response and the induced antibody titers, these outcomes would necessarily have occurred in the methods disclosed by Sheldon et al.
Sheldon et al differs from the instant invention in that they do not disclose that the toxoids are at a purity of at least 90% and they do not disclose that the humans are seronegative for toxins A and B.
It would have been obvious to one of ordinary skill in the art to use toxoids of at least 90% purity because mere purity of a product, by itself, does not render the product nonobvious. Factors to be considered in determining whether a purified form of an old product is obvious over the prior art include whether the claimed chemical compound or composition has the same utility as closely related materials in the prior art, and whether the prior art suggests the particular form or structure of the claimed material or suitable methods of obtaining that form or structure. In re Cofer, 354 F.2d 664, 148 USPQ 268 (CCPA 1966). In the instant case, it is self-evident that one would desire a highly purified product in a vaccine that is meant to be injected into a human. This is particularly so since the vaccine is a toxoid that must be isolated from bacterial cellular contents and chemically inactivated. Methods of purifying toxoids are well known and regularly used in the art, as evidenced by the numerous toxoid vaccines that are in use.
With regard to administration of the toxoid vaccine to seronegative individuals, it is clear that protection of any at-risk human from C. difficile infection is desirable and this includes people who have not been exposed to the toxins previously.
One would have had a reasonable expectation of success because toxoid vaccines are standard in the art and purification of toxoids is well known. Further, there is no reason to think that the vaccine would not work in seronegative individuals.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brian J Gangle whose telephone number is (571)272-1181. The examiner can normally be reached M-F, 9-6:30.
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/BRIAN GANGLE/Primary Examiner, Art Unit 1645
