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 response and amendment to the claims filed 1-28-2026 has been entered into the record. Claims 1-20 are pending.
Sequence Requirements
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 C.F.R. § 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 C.F.R. § § 1.821-1.825 for the reason(s) set forth below. Full compliance with the sequence rules is required in response to this office action.
Page 22 contains the following sequences which are not followed by an appropriate sequence identifier.
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Election/Restrictions
Applicant’s election of Group I and species OmpA from B. pertussis in the reply filed on 1-28-2026 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)).
Claims 4, 5 and 11-20 are withdrawn as drawn to non-elected inventions. Claims 1-3 and 6-10 are under examination.
Information Disclosure Statement
The information disclosure statements have been considered. Initialed copies are enclosed.
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.
Claims 1-3 and 6-10 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 immunizing a mammalian patient against infection by Pesudomonas aeruginosa comprising administering an OmpA protein of Bordetella pertussis, it does not reasonably provide enablement for cross-protection for other claimed bacterial species and for use of fragments of OmpA or percent identical 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 use the invention commensurate in scope with these claims.
The claims are drawn to a method for producing cross-protection to a bacterial pathogen that is not Bordetella pertussis by the administration of Bordetella pertussis OmpA or fragment thereof. The claim reads on the use of whole cell vaccines or purified proteins or fragments. The antigen fragment of the broad claims are without limitation and are limited to specific regions with percent variation in claim 6. The specification teaches that immunization with whole cell Bordetella pertussis or purified recombinant OmpA, provides for cross-protection from infection by Pseudomonas aeruginosa. The specification does not demonstrate cross-protection from any other bacterial pathogen recited in claims 2 and 9. The specification while identifying areas of homology with other OmpA proteins and suggests that these fragments may be cross-protective, no evidence is presented with the fragment per se or any percent identical variant thereof. The specification does not identify the protective epitope (i.e. fragment) on B. pertussis OmpA. While the specification discloses fragments of SEQ ID NOS:9-11, it does not set forth if they are cross-protective as claimed. Additionally, the specification does not teach which residues in the fragments of SEQ ID NOS:9-11 can be varied and still provide for cross-protection. No fragment has been identified as cross-protective, the specification is speculative based upon percent identity among OmpA variants, and the examples are prophetic (Examples 11-15). The cross-protective peptide epitopes are not disclosed, antibodies or therapeutic antibodies binding any disclosed peptide fragment or SEQ ID NOS:9-11 of OmpA (B. pertussis) have not been demonstrated to provide for a therapeutic effect of cross-protection in any other Bordetella species or in the genera/species set forth in claims 2 and 9. The courts have held that the disclosure is insufficient when testing is necessary to determine the actual use or possible lack of use (In re Kirk and Petrow 153 USPQ 48 (CCPA 1967).
The specification does not disclose that the disclosed fragments of SEQ ID NOS:9-11 are epitopes that provide for cross-protection or generate cross-protective antibodies. In fact, the specification does not identify which peptide epitopes on pertussis OmpA have protective antibodies bind such that the skilled artisan would readily ascertain that the fragment/regions would themselves generate cross-protective immunity as claimed. Is necessarily follows that since the specification does not provide for cross-protective activity of the fragments of SEQ ID NOS:9-11, then a distinguishing and identifying features of a representative number of members of the percent identical variants to those OmpA regions as cross-reactive protective epitopes has not been demonstrated. Such as a correlation between the structure of the claimed OmpA epitope and its recited function (generating an immune response with cross-reactivity and protection from infection with other non-pertussis bacterial pathogens), so that the skilled artisan could immediately envision, or recognize at least a substantial number of members of the claimed genus. Moreover, the specification fails to disclose which chemical structures are essential to the function of the epitopes found in the claimed microbial antigens so that the cross-reactivity of the microbial antigenic fragment can be ascertained/maintained.
The specification fails to teach where the cross-protective epitopes are present in B. pertussis OmpA such that the skilled artisan could make and use the fragments for cross-protective immunization as claimed. The specification does not correlate the cross-protective function of the immune response against full-length pertussis OmpA with the structure of the fragments as claimed. The specification does not describe where the T and B cell epitopes are present on native OmpA of pertussis. The identification of epitopes is an inherently empirical process and methods of identification of such using a variety of algorithms in the art is unpredictable. The specification fails to disclose which chemical structures are essential to the function of the full-length protein that has the property of raising a cross-protective immune response against P. aeruginosa, much less any other recited bacterial genus/species recited in claim 2. The specification does not teach what are the specific peptide epitopes comprising fragments of OmpA that are cross-protective and were essential for the function of raising an immune response against OmpA to generate a cross-protective bacterial immune response as claimed. As evidenced by Greenspan et al. (Nature Biotechnology 7: 936-937, 1999), defining epitopes is not as easy as it seems. Greenspan et al. recommends defining an epitope by the structural characterization of the molecular interface between the antigen and the antibody is necessary to define an "epitope" (page 937, column 2). According to Greenspan et al., an epitope will include residues that make contact with a ligand but are energetically neutral, or even destabilizing to binding. Furthermore, an epitope will not include any residue not contacted by the antibody, even though substitution of such a residue might profoundly affect binding. Accordingly, it follows that the immunoepitopes (of an antigen) that can elicit an antibody response to a given pathogen can only be identified empirically. While the art can conventionally scan for potential contiguous antibody epitopes using conventional art accepted algorithms (Greenbaum et al, Journal of Molecular Recognition, 20(2):75-82, 2007), these methods do not identify discontinuous epitopes which are identified by crystallization of antibody/antigen complexes. The quality of the methods for B cell epitope prediction was widely considered to be too poor to be employed as a reliable tool by immunologists (paragraph spanning pages 75-82). The art recognizes that defining epitopes is not easy and there is a confusing divergence between the textbook definition of epitope and the definition that is in use in published descriptions of experimental investigations (Greenspan et al, Nature Biotechnology 17:936-937, 1999). The art recognized that single-scale amino acid propensity profiles could not be used to predict epitope location reliably (Blythe et al, Protein Science 14:246-248, 2005). Therefore, even with art tools, it would be unpredictable to use those tools to attempt to identify conserved regions that were important for eliciting a cross-protective bacterial immune response as claimed. Further testing would be required to determine additional cross-protection for other bacterial species and efficacy of any fragment or variant thereof. This testing is undue and unpredictable.
The specification does not describe those residues that could be changed and still preserve the ability to generate a cross-protective immune response as claimed. The art has indicated that the retention of the specificity following one or more amino acid substitutions in a polypeptide is another factor that has been shown to be unpredictable in the art. For instance, McGuinnes et al. (Mol. Microbiol. 7: 505-514, Feb 1993) taught that “[a] single amino acid change within an epitope, or an amino acid deletion outside an epitope, were both associated with loss of subtype specificity resulting from a change in the predicted conformation at the apex of the loop structure” in case of a meningococcal polypeptide (see abstract). Similarly, McGuinnes et al. (Lancet 337: 514-517, March 1991) taught that a point mutation generating a single amino acid change in a P1.16-specific epitope in the VR2 region of the porA gene of a strain of Neisseria meningitidis of subtype P1.7,16 resulted in “striking changes in the structural and immunological properties of the class 1 protein” of this isolate (see abstract and page 514). For instance, Houghten et al. (New Approaches to Immunization, Vaccines86, Cold Spring Harbor Laboratory, p. 21-25, 1986) taught the criticality of individual amino acid residues and their positions in peptide antigen-antibody interactions. Houghten et al. state (see page 24): "One could expect point mutations in the protein antigen to cause varying degrees of loss of protection, depending on the relative importance of the binding interaction of the altered residue. A protein having multiple antigenic sites, multiple point mutations, or accumulated point mutations at key residues could create a new antigen that is precipitously or progressively unrecognizable by any of the antibodies in the polyclonal pool." The courts have held that it is the specification, not the knowledge of one skilled in the art, that must supply the novel aspects of an invention in order to constitute adequate enablement. (Genentech Inc. v. Novo Nordisk A/S Ltd., 42 USPQ2d 1001). Moreover, the specification must have been enabling at the time the invention was made and developments after the time of filing are of no consequence to what one skilled in the art would have believed at the time of filing (In re Wright, 27 USPQ2d 1510).
In view of the unpredictability of the art, the lack of teachings of the specification, and in the absence of further guidance from Applicants it would require undue experimentation on the part of the skilled artisan to make and use the claimed OmpA pertussis polypeptide and fragments thereof as claimed.
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.
Claims 1, 2, 7, 8, 9 and 10 are rejected under 35 U.S.C. 102(a)(1) as being clearly anticipated by Locht et al (US 9,180,178, issued November 10-2015).
Locht et al teach that immunization with BPZE1 (a Bordetella pertussis live attenuated whole cell strain) protected against B. parapertussis infection (see column 16, Lines 20-39). Locht et al teach that the BPZE1 can be formulated with physiological excipients including phosphate buffered saline, emulsions and adjuvants. Adjuvants can comprise MDP, IL-12, aluminum phosphate, aluminum hydroxide, alum and /or MontanideTM can be used (column 9, lines 1-10). Locht et al teach that vaccines can be administered by subcutaneous, intradermal, intramuscular or intravenous, oral, intranasal or inhalation (column 9, lines 24-32). Immunization with PBEZ1 inherently comprises B. pertussis OmpA and GroEL(i.e. the second antigen to the bacterial pathogen). Locht et al teach that use of BPZE1 provides for mucosal vaccination having the advantage for heterologous expression and presentation of antigens. BPZE1 can be used for the production of antigens to which systemic responses are desired (see column 23, lines 44-55). As such, the method of the prior art anticipates the claims herein.
The whole cell. B. pertussis vaccine inherent provides for the claimed cross-protection absent convincing evidence to the contrary. "It is a general rule that merely discovering and claiming a new benefit of an old process cannot render the process again patentable." In re Woodruff 919 F.2d 1575, 1578 (Fed. Cir. 1990). When "a claimed new benefit or characteristic of an invention otherwise in the prior art" is an inherent property of the old invention, "the new realization alone does not render the old invention patentable." Perricone v. Medicis Pharm. Corp., 432 F.3d 1368, 1377 (Fed. Cir. 2005). "[A] limitation or the entire invention is inherent and in the public domain if it is the 'natural result flowing from' the explicit disclosure of the prior art." Id., citations omitted. As summarized in Perricone, id. at 1375-76:A single prior art reference that discloses, either expressly or inherently, each limitation of a claim invalidates that claim by anticipation. Minn. Mining & Mfg. Co. v. Johnson & Johnson Orthopaedics, Inc., 976 F.2d 1559, 1565 (Fed. Cir. 1992). Thus, a prior art reference without express reference to a claim limitation may nonetheless anticipate by inherency. See In re Cruciferous Sprout Litig., 301 F.3d 1343, 1349 (Fed. Cir. 2002). "Under the principles of inherency, if the prior art necessarily functions in accordance with, or includes, the claims limitations, it anticipates." Id. (quoting MEHL/Biophile Int 'l Corp. v. Milgraum, 192 F.3d 1362, 1365 (Fed. Cir. 1999). Moreover, "[I]nherency is not necessarily coterminous with knowledge of those of ordinary skill in the art. Artisans of ordinary skill may not recognize the inherent characteristics or functioning of the prior art." Id.; see also Schering Corp. v. Geneva Pharms., 339 F.3d 1373, 1377 (Fed. Cir. 2003) (rejecting the contention that inherent anticipation requires recognition in the prior art) (citing In re Cruciferous Sprout Litig., 301 F.3d at 1351; MEHL/Biophile, 192 F.3d at 1366). "Thus, when considering a prior art method, the anticipation doctrine examines the natural and inherent results in that method without regard to the full recognition of those benefits or characteristics within the art field at the time of the prior art disclosure." Id. at 1378.
Citation of Relevant Prior Art
Locht (Clinical Microbiology and Infection, 22:S96-S102, 2016) teaches that BPZE1 vaccination protected against B. parapertussis infection and B. bronchiseptica infection (see page 599, column 1, last paragraph and page 599 column 2 second paragraph).
Conclusion
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/Patricia Duffy/Primary Examiner, Art Unit 1645
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