DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s election without traverse of group I, claims 1-21, in the reply filed on 11/26/25, is acknowledged. Applicant has further elected VEGF-A121 as the species of VEGF-A isoform, the species of cysteine linked isoform from claim 4, and SEQ ID NO: 18 as the species of VEGF-A sequence. Claims 22-24 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention. Claims 5-15 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to non-elected species.
Claims 1-4 and 16-21 are being acted upon.
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 1-4 and 16-21 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 and 4 recite “the second cysteine”, “the fourth cysteine” etc. throughout the claims. Claim 1 also recites the limitation “the polypeptide chain” in cline 3.There is insufficient antecedent basis for these limitations in the claims. It is also unclear what “function” is required in the present claims. The specification on page 4 discloses that a functional mutant of VEGF-A differs from a natural variant on its binding to VEGFR2, and the fact that it does not induce the signal transduction associated with the receptor binding. It appears therefore that the claims do not require that the VEGF-A functions in inducing VEGRR2 signaling, but it is unclear what “function” is required. Does it bind to some other receptor? Is it required to function as an immunogen or an antagonist? The scope of the claims cannot be established. Claim 2 is indefinite for the same reasons, regarding the “function” required of the mutant.
The claims are also indefinite in that it is not clear if it they require a dimeric polypeptide or not. Claim 1 recites that the seventh and eight cysteine residues “are only found forming intermolecular bonds”. Intermolecular bonds would require that a polypeptide is bonded to another separate polypeptide chain. However, claim 1 only recites “a polypeptide” comprising a functional mutated form of VEGF-A. Are the claims intending to encompass a single VEGF-A polypeptide chain, wherein the seventh and eight cysteines are unbonded but capable of forming intermolecular bonds? Or do the claim actually require a structure of two separate polypeptide chains that are linked via the intermolecular bonds. The scope of the claim is unclear and indefinite.
Claim 4 is indefinite in the recitation that the “the seventh cysteine of two polypeptide chains, the eight cysteine of two polypeptide chains and the last cysteine of two polypeptide chains are linked forming intermolecular disulfide bridges”. There is insufficient antecedent basis for the limitation of “the cysteines of two polypeptide chains” and also no antecedent basis of “the last cysteine”. Claim 1, from which the claim ultimately depends is directed to “a polypeptide” comprising a mutated form of an isoform of human VEGF-A. It is not clear what the “two polypeptide chains” encompasses. Is it another VEGF-A polypeptide, or could it be a distinct type of polypeptide? Furthermore, it is not clear what types of linkage are encompassed between the seventh, eight and last cysteines. For example, do the seventh cysteines of two polypeptide chains have to be linked to each other, or could the seventh cysteine of one polypeptide chain be linked to the last cysteine of another polypeptide chain? Do the claims mean to imply that the 3 cysteines are linked in a single linkage? The scope of the claim is unclear and indefinite.
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 1-4, 16-17, 19-21 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. Specifically, there is insufficient written description to demonstrate that applicant was in possession of the claimed genus of polypeptides comprising a functional mutated form of an isoform of human VEGF-A..
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.
The instant claims are directed to a genus of structurally divergent mutated VEGF-A polypeptides. The claims require that the VEGF-A polypeptides are “functional”, and wherein disulfide bridges occur in a particular arrangement between eight cysteine residues. This would encompass a large genus of structurally distinct polypeptides. For example, the claims would encompass numerous mutations, i.e. substitutions, additions or deletions, in any combination, wherein the polypeptides exhibit a genus of functions ranging from receptor binding, immunogenic function, or antagonist function. The claims also encompass mutations that function to rearrange disulfide bridges in the claimed genus of arrangements, i.e. deleting or adding cysteine residues to provide for the particular intramolecular and intermolecular disulfide bridges in the claimed arrangement. This would also encompass a large genus of structurally distinct proteins with different numbers and arrangement of cysteine residues and disulfide bonds. For example, see Keck (of record) which teaches the sequence of human VEGF-A isoforms, such as VEGF-A165, which has 13 cysteine residues. The present claims encompass, for example, deletion of native C1 (cysteine 1), such that the mutant VEGF-A has 12 cysteines, wherein C1 of the mutant has a position corresponding to C2 in the native VEGF-A. One could also delete C1 and C2 of the native VEGF-A to create a mutant wherein C1 of the mutant corresponds to C3 of the native VEGF-A and so on. Thus, the claims encompass an essentially unlimited genus of structurally distinct proteins having disulfide bonds at any position and rearranged in a genus of different conformational structures.
Furthermore, the state of the art is such that protein chemistry is one of the most unpredictable areas of biotechnology. Whisstock et al (Quarterly Review of Biophysics, 2003, 36, pp307-340) teach that the prediction of protein function from sequence and structure is a difficult problem, because homologous proteins often have different functions. Even single amino acid changes in a proteins amino acid sequence can have dramatic effects on protein function. For example, Wang et al., 2001, show that a single amino acid determines lysophospholipid specificity of the S1P1 (EDG1) and LPA1 (EDG2) phospholipids growth factor receptors (e.g., abstract). These references demonstrate that even a single amino acid substitution or what appears to be an inconsequential chemical modification will often dramatically affect the biological activity and characteristic of a peptide. Furthermore, the formation of disulfide bonds and protein folding is very complex, and is influenced by non-covalent interactions and the manner in which residues of a protein are arranged (see Qin, 2005). The specification does not provide a correlation between structure and “function” as broadly claimed, nor for the particular arrangement of disulfide bridges. The specification discloses a single species of VEGF-mutant in SEQ ID NO: 2, which represents human VEGF-A121 with R82, K84, and H86 are mutated to E.. The specification discloses a cell culture process by which SEQ ID NO: 2 can be purified from bacteria, wherein the process results in a mixture of different disulfide bonded arrangements in the protein (these are shown in the sequence listing as SEQ ID NO: 18-23, which all have the same primary amino acid sequence, i.e. SEQ ID NO: 2, but in the description section of the sequence listing indicate certain disulfide linkages). However, this is not sufficiently representative of the broad genus of VEGF-A polypeptides encompassed by the present claims. For example, SEQ ID NO: 2 has all of the cysteines arranged in the manner as found in native VEGF-A121 (i.e. C1 of the mutant is the same position as found in C1 of native VEGF-A121, and so on). This is not sufficiently representative of the genus of different mutants encompassed by the present claims
The instant application has not provided a sufficient description showing possession of the necessary 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 genus of proteins encompassing various structures and functions. Further, the Court has interpreted 35 U.S.C. §112, first paragraph, to require the patent specification to “describe the claimed invention so that one skilled in the art can recognize what is claimed. Enzo Biochem, Inc. v. Gen-Probe Inc, 63 USPQ2d 1609 and 1618 (Fed. Cir. 2002).
In evaluating whether a patentee has fulfilled this requirement, our standard is that the patent’s “disclosure must allow one skilled in the art ‘to visualize or recognize the identity of’ the subject matter purportedly described.” Id. (quoting Regents of Univ. of Cal. v. Eli Lilly & Co., 43 USPQ2d 1398 (Fed Cir. 1997)).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Also, it is noted that the Court has held that the disclosure of screening assays and general classes of compounds was not adequate to describe compounds having the desired activity: without disclosure of which peptides, polynucleotides, or small organic molecules have the desired characteristic, the claims failed to meet the description requirement of § 112. See University of Rochester v. G.D. Searle & Co., lnc., 69 USPQ2d 1886,1895 (Fed. Cir. 2004).
Meeting the written description threshold requires showing that the applicant was in “possession” of the claimed invention at the time of filing. Vas-Cath, 935 F.2d at 1563-1564. Support need not describe the claimed subject matter in exactly the same terms as used in the claims. Eiselstein v. Frank, 52 F.3d 1035, 1038 (Fed. Cir. 1995). This support cannot be based on obviousness reasoning – i.e., what the written description and knowledge in the art would lead one to speculate as to modifications the inventor might have envisioned, but failed to disclose. Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997). Ariad points out, the written description requirement also ensures that when a patent claims a genus by function, the specification recites sufficient materials to accomplish that function - a problem that is particularly acute in biological arts." Ariad, 598 F.3d at 1352-3.
Thus, one of skill in the art would conclude that the specification fails to provide adequate written description to demonstrate that Applicant was in possession of the claimed genus. See Eli Lilly, 119 F. 3d 1559, 43, USPQ2d 1398.
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 1-3, 19-21 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO2010090523 (of record), in view of Czajkowsky, 2012.
WO2010090523 teaches a mutant of human VEGF-A121 isoform with 6 cysteines having a sequence of: YC1HPIETLVDIFQEYPDEIEYIFKPSAVPLMRC2GGSC3NDEGLE C4VPTEESNITMQIMRIKPHQGQHIGEMSFLQHNKC5EC6RPKKD,
wherein C1 is linked to C4, C2 is linked to C5, and C3 is linked to C6, i.e. a polypeptide wherein the second (C2) and fourth (C4) cysteines of the polypeptide are only found as part of intramolecular bridges (see pages 3 , 9, 16, and see page 43). WO2010090523 teaches that the VEGF-A polypeptide can be coupled to a carrier protein and can be in the form of immunogenic pharmaceutical composition with a carrier or adjuvant (See page 28, in particular). WO2010090523 teaches CFA/IFA as an adjuvant (i.e. oil adjuvants, see examples). WO2010090523 teaches that the VEGF-A polypeptides have excellent immunological properties and can be used as a vaccine (i.e. they are “functional”, see page 6, in particular). WO2010090523 teaches that the mutant does stimulate VEGFR2, i.e. mutation of amino acids involved in binding to VEGFR2 receptor.
The reference differs from the claimed invention in that it does not explicitly teach a seventh and eight cysteine only found as part of intermolecular bonds.
Czajkowsky teach the use of an Fc domain as a carrier protein for improving vaccination, since it targets the linked protein to APCs for inducing an immune response (see pages 1019-1021, in particular). Czajkowsky explains that the Fc region is linked to the C-terminus of another polypeptide, and that it forms homodimers via two disulphide bonds between the two polypeptide chains (i.e. intermolecular bonds, see Fig. 1, in particular).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made use the Fc region, as taught by Czajkowsky, as the carrier protein for the immunogenic vaccine VEGF-A compositions of WO 2010/0090523. The ordinary artisan at the time the invention was made would have been motivated to do so with a reasonable expectation of success, because. Czajkowsky teaches the use of an Fc domain as a carrier protein improves vaccination, since it targets the linked protein to APCs for inducing an immune response. Doing so would result in a polypeptide comprising said VEGF-A and further comprising an Fc region that comprises two additional cysteine residues (i.e. a seventh and eight cysteine residue), wherein said cysteine residues only form intermolecular disulfide bonds.
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.
Claim(s) 1-4 and 16-21 is/are rejected under 35 U.S.C. 102(a)(1) as anticipated by Morera, 2008 (of record), as evidenced by Yero, 2006 and Jian, 2010 (of record), or in the alternative, under 35 U.S.C. 103 as obvious over Morera, 2008 (of record), in view of Yero, 20060 and Jian, 2010 (of record).
Morera teaches a mutant of human VEGF-A121 isoform in which residues R82, K84, and H86 are mutated to E (mutation of residues involved in VEGFR binding, see page 383, in particular). Morera teach expressing said mutant VEGF-A from the M238 vector, which includes an N-terminal fusion to the P64K protein and a histidine C-terminus tail (See pages 382-383, in particular). As evidenced by Yero, the p64K protein of the M238 expression vector has a sequence identical to residues 1-59 of SEQ ID NO: 18 (and SEQ ID NO: 24) of the instant application, and the C-terminal histidine tail has a sequence identical to residues 181-190 of SEQ ID NO: 18 of the instant application. Furthermore, residues 60-180 of SEQ ID NO: 18 represent human VEGF-A121 with said R82, K84, and H86 mutated to E mutations. Therefore, the VEGF-A mutated polypeptide of Morera inherently comprises SEQ ID NO: 18. See also pages 15-16 of the instant specification, which explain that VEGF-A was expressed from the PM238 in Morera and has the sequence of SEQ ID NO: 2, which is identical to SEQ ID NO :18 of the present claims. Therefore, the VEGF-A mutated polypeptide of Morera inherently comprises SEQ ID NO: 18. Morera teaches said VEGF-A as a pharmaceutical vaccine composition with aluminum hydroxide (i.e. aluminum salts) adjuvant for inducing an immune response (i.e. “functional” VEGF, see page 384, in particular).
Regarding the disulfide bond arrangement of the present claims, Jian teaches that under normal conditions, 100% of proteins do not form a native disulfide linked structure, and that X-isomers with rearranged disulfide bonds are also present in minor amounts in equilibrium with native protein conformation. (see Fig 1, in particular). In other words, Jian teaches that disulfide scrambled X-isomers are present under normal conditions in very minor amounts. Therefore, the disulfide bond arrangements would be an inherent property of the VEGF-A preparation of Morera, which has the exact same primary amino acid sequence of the instant claims, and a small minority of the VEGF would form X-isomers having the disulfide conformation of the instant claims under equilibrium.
Alternatively, Jian also teaches enhanced formation of such x-isomers of VEGF isomers by a process of oxidative refolding, which results in disulfide scrambling to created non-native disulfide proteins of VEGF. Jian teaches that doing so is advantageous since it enhances immunogenicity. Therefore, it would also be obvious to use the x-isomer inducing conditions of Jian, for preparing the VEGF polypeptide of Morera since Jian teaches that it is advantageous since it enhances immunogenicity. The instant specification teaches that oxidative re-naturation of the VEGF-protein of SEQ ID NO: 2 results in a mixture of disulfide isoforms, including the isoform of Claim 4. Therefore, the claimed disulfide arrangements would be latent property of following the suggestions of the prior art.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY E JUEDES whose telephone number is (571)272-4471. The examiner can normally be reached on M-F from 7am to 3pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached on 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Amy E. Juedes
Patent Examiner
Technology Center 1600
/AMY E JUEDES/Primary Examiner, Art Unit 1644