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 .
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 .
Status of the Claims
Claims 1-15 are currently pending in the Application and are examined on the merits below.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claim Rejections - 35 USC § 112
Claims 1-12, 14, 15 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.
In instant claims 1, 14 and rejected dependent claims 2-7 the Applicant claims pharmaceutical composition comprising a monoclonal antibody which may variably specifically recognize a large portion of the PRDX4 protein (residues 81-271 of a 271 amino acid sequence) .
In rejected claims 8, dependent on claims 1 and independent claim 14 Applicant provides structural information relating to the full length VH and VL fragments of the particular antibody but describes that antibody may vary up to 85% in sequence homology to the indicated sequences. Applicant thus provides variability in the critical CDR regions of the provided VH and/or VL fragments and would claim a genus of antibody but providing a non-representative particular set of antibody, antibody which all appear to share identical CDR-VH3 and CDR-VL3 sequences.
In rejected claims 9, 15 Applicant provides unique CDR region composition of the claimed antigen binding molecules however in embodiment “k” provides structurally undefined “antibody which binds to the same epitope as that in the human PRDX4 protein to which any one of the antibodies (a) to (j) bind”. The applicant thereby attempts to define the antibody by what it binds to and not what it is.
Likewise linked method claims 10-12 are rejected as dependent on a structurally undefined monoclonal antibody which is define by epitope bound and not what the antibody actually comprises.
Applicant provides no structural information regarding the particular antibody of the claimed invention attempting to describe the antibody by what it binds to, not what it is. Applicant claims therefore a broad genus of structurally diverse antibody which may bind to a significant epitope sample of the PRDX4 protein while providing a limited number of examples of antibody which satisfy the claimed genus all of which share particular VH-CDR3 and VL-CDR3 sequences.
Therefore regarding the claims, the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See MPEP 2163(II)(A)(3)(a)(ii). The state of the art with regards to antibody structure-function correlations is such that antibody variable regions (VH and VL are composed of a heavy and light chain, each involved in providing binding specificity. Variability in the antigen binding site is achieved by V(D)J recombination via heavy and light chain pairing, with the most diverse regions being the 6 CDR regions in the heavy and light chain. While the heavy chain is the most diverse, light chains are also important for binding specificity of antibodies, and swapping light chains can also change the antigen specificity of the antibody. For an example of the complexity, diversity, and unpredictability of antigen binding derived from antibody molecules one can look to the disclosure of Rabia et al (Biochemical Engineering Journal 137 (2018) 365–374), which teaches that the maximal chemical diversity of antibody CDRs is unimaginably large and is extremely challenging to define the sequence determinant of antibody specificity (see page 4). Rabia also teaches that single point mutations in CDR regions can alter binding specificity, and that such mutations are highly context dependent, and the same mutations can lead to opposite impacts on antibody specificity in different antibody sequences (see page 5, in particular).
For a further example of the complexity, diversity and unpredictability of binding derived from protein-protein interactions one may look to the disclosure of Lloyd et al. (Protein Engineering, Design & Selection vol. 22 no. 3 pp. 159–168, 2009).With respect to viable binding molecules (antibody) to a particular antigen (protein), Lloyd illustrates the tremendous diversity of VH and VL pairings and also usage of diverse repertoire of the highly variable antibody VH and VL sequences corresponding to what amounts to a diverse variable and unpredictable mix of amino acid sequences which bind to antigen through protein-protein interactions. (see Lloyd fig 1, 2, and p167 paragraphs 1-2)
Furthermore, of particular relevance to the instant claimed epitope binding function of the (antibody) binding molecule the disclosure of Goel et al (Journal of Immunology (2004) 173 (12): 7358-7367) describes the structural features of 3 antibody which bind a particular epitope of a 12mer peptide which mimics mannopyranoside carbohydrate molecule. The three antibody which recognize the same epitope comprise widely divergent CDR compositions when compared side by side (figure 3 for reference). Thus defining an antibody by the binding target epitope by disclosing two antibody which comprise particular set of CDR 1-3 of the heavy and light chain does not allow one to predictably envision the structural composition of the entire genus as claimed in such a way.
Thus, one of skill in the art would conclude that applicant has not disclosed a sufficient representative number of species of the claimed genus to satisfy the written description requirement.
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.
Claims 1-4, 10-12, 13 are rejected under 35 U.S.C. 103 as being unpatentable over Georges et al (WO200707221) and further in view of Powis et al (Annu. Rev. Biophys. Biomol. Struct. 2001. 30:421–55).
Instant claim 1 describes a pharmaceutical composition which comprises a monoclonal antibody which binds “to human PRDX4 present on the cell surface of a cancer cell”. Applicant therefore appears to attempt to differentiate non-malignant cells which either secrete the PRDX4 protein into the extracellular space or retain the protein intracellularly and do not normally express “cell surface” PRDX4 from malignant cells.
Regarding the instant claim 1 the disclosure of Georges describes antibodies, both polyclonal and monoclonal which recognize the presence of for example PXDR4 on the surface of cancer cells (table 1, 0077). As supported by the disclosure of Powis, the thioredoxin peroxidase-4 nomenclature is a synonym for the PRDX4 molecule, also designated as human AOE372 molecule (Powis P429, paragraph 2). Therefore Georges clearly discloses that PRDX4 is a protein of interest found on the surface of cancer cells.
Antibodies of the invention of Georges may be utilized for diagnosis, detection and prevention of cancer for example. Pharmaceutical compositions are additionally disclosed (0120-0130). It would therefore be obvious to provide a pharmaceutical composition comprising an antibody which recognizes the claimed epitope of PRDX4 as the near full length signal peptide cleaved molecular entity for the purposes of detecting and/or treating specifically cancer cells which may express the antigen on the cell surface. The pharmaceutical composition may be utilized in a treatment or diagnostic assay.
Regarding the instant claims 2, 4 for example antibody of the invention of Georges may be conjugated to immunotoxins as a “therapeutic component” of an antibody conjugate (0114). Such a conjugate would be considered thereby “cytotoxic” as capable of killing a neoplastic cell directly as indicated by Georges.
Regarding the instant claim 3 and the description that the composition “has ADCC or CDC” the disclosure of Georges indicates that monoclonal antibody (0079) of the invention may be of any isotype of the principal immunoglobulin classes such as IgM, IgG, IgD, IgE or IgA. Subclasses for example include IgG1, IgG2, IgG3, IgG2a, IgG2b, IgG3. The subclass IgG1 for example is known to provide Fc gamma receptor engagement on effector immune cells and it would be obvious to utilize such an isotype to provide antibody mediated cellular cytotoxicity for the purposes of differentially eliminating malignant cells expressing PRDX4 on their cell surface for example as disclosed by Georges.
Instant claim 10 provides a method of treating cancer through administration of the pharmaceutical composition of claim 1. Claim 11 describes that the cancer expresses PRDX4 on the cell surface and claim 12 indicates that the cancer may be ovarian cancer for example.
As indicated above the disclosure of Georges provides monoclonal antibody which recognize PXDR4 protein. The disclosure further provides treatment protocols for ovarian carcinoma and specific examples of preclinical models of ovarian cancer treated with therapeutic monoclonal antibody of the invention directed to PXDR4 (0012)(example 10)(0163-0165). It would therefore have been obvious to utilize a monoclonal antibody which targets the PXDR4 antigen found on the surface of ovarian carcinoma cells for example for the purposes of treating a cancer which selectively expresses the PXDR4 antigen on its cell surface as compared to normal non-malignant cells. Such a method would beneficially target and reduce malignant cell burden in an individual thereby treated.
Claim 13 describes a “method of determining” whether a human subject may suffer from cancer through determination of whether PRDX4 is “present on the cell surface of cancer cells comprised by said sample”.
Regarding the claim 13, the disclosure of Georges (WO200707221) is concerned with surface marker directed cancer therapeutics. Protein targets which are found on the surface of cancer cells are identified, with PRDX4 protein particularly disclosed as a known target molecule found on the surface of cancer cells (0009, Table 1, example 10). Relevant to the instant claim 13, the disclosure provides diagnostic assays for cell surface expression are useful for selecting subjects which may have neoplastic cells in subject samples (0050). It would therefore be obvious to develop a method of determining whether a subject has a neoplasm based on the surface expression of PRDX4 as a molecule known to be expressed intracellularly in normal cells and on the cell surface of particular cancer cells as disclosed by Georges.
Conclusion
Summary: No claims are allowed
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/BRIAN HARTNETT/Examiner, Art Unit 1644
/DANIEL E KOLKER/Supervisory Patent Examiner, Art Unit 1645