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 .
Claims 70-84 are under consideration in the instant Office Action.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Specification
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required: Newly amended claims 70-72 filed on12/12/2023 requires residues 22-430 of SEQ ID NO:66 which is new matter. The residues 22-430 of SEQ ID NO:66 is not present in the originally filed claims or the instant specification. The 22-430 residue range is not listed for SEQ ID NO: 66, but rather only for SEQ ID NO: 69, see instant specification at [032] and [168].
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.
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 70-84 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. This rejection encompasses new matter rejection and a protein % identity written description rejection.
There is no proper antecedent basis nor contemplation in context that is disclosed within the specification at the time of filing the instant specification for the recitation for residues 22-430 of SEQ ID NO:66. The instant claims require this limitation, residues 22-430 of SEQ ID NO:66. There is no support for this limitation in the original set of claims or the instant specification or even in the provisional of parent applications, thereby, constituting new matter.
Further, the instant claims are directed to fusion polypeptide comprising a neuropilin (NRP1) polypeptide consisting of an amino acid sequence having at least 90% identity with residues 22-430 of SEQ ID NO:66 and a fragment crystallizable FC domain or portion thereof fused to amino-terminal of the NRP1. The 10% difference in the amnio caid 22-430 of NRP1 are not disclosed and the fragment crystallizable FC domain or portion thereof is not disclosed in the instant claims or instant specification. The % identity of NRP1 can occur in any number between one forty sites, with any number of amino acids being substituted at any residue. This reads on up to 40 point mutations or removal of large fragments. The other protein that is part of the fusion protein, fragment crystallizable FC domain includes a portion thereof that is not fully disclosed. There is no specific sequence for the fragment crystallizable FC domain or portion thereof or what specifies or antibody type this FC domain is included in the instant product. The NRP1 proteins have specific functions. The neuropilin-1 is a receptor for both Sema3A and VEGF and is the only receptor for Sema3A. The extracellular domain of NRP1 contains two domains with homology to complement components C1r and C1s (CUB domains, also called “a1” and “a2”) at the amino terminus, followed by two coagulation factor V/VIII domains (CF V/VIII, also called “b1” and “b2”), and one C-terminal MAM domain (also called “c”). Each of the Npn-1 extracellular domains are required for biological activity mediated by Sema3A, but only the CUB domains (a1a2 domains) are required for binding to the same domain of Sema3A. A Npn-1 variant lacking both a1 and a2 CUB domains is incapable of binding to Sema3A but does bind to VEGF since b1, b2 and c domains are still present. The instantly claimed method of using this broad genus of fusion protein to reduce ocular inflammation demands a specific function with a very broad genus of possible of fusion proteins. The specification discloses NRP-1 variants as having the required functions. However, the claims encompass a far broader genus of proteins. The claims recite NRP1 proteins having up to 40 mutation sites, although not all of the possible substitutions may be capable of the required functions. The selection of 40 mutants with variable amino acids could yield thousands of possible proteins, and picking from all of the possible amino acids for each of the mutation sites would generate millions of possible variant proteins. There is no disclosure of structure/function for all of these possible fusion proteins. The claims require that the protein exhibit specific functional characteristics, but the specification provides no minimal guidance regarding which variants are capable of the required function. Additionally, Applicant has not recited all the possible sequences that encompass the variability of up to 10% difference in the NRP1 protein sequence. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim. 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.)
The skilled artisan cannot envision the detailed chemical structure of the encompassed polypeptides, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class.
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that:
...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc. , 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2datl966.
Protein chemistry is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number or location of mutation will have on a protein (such as NRP1) As taught by Skolnick et al (Trends Biotechnol. 2000 Jan;18(1):34-9, instant PTO-892), sequence based methods for predicting protein function are inadequate because of the multifunctional nature of proteins (see e.g. abstract). Further, just knowing the structure of the protein is also insufficient for prediction of functional sites (see e.g. abstract). Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cells (see e.g. page 34, right column). Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works (see e.g. page 34, right column).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990, in instant PTO-892) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
One key issue is the prediction of protein function based on sequence similarity, which could be one way to identify the functional proteins that are useful in the instant claims. Kulmanov et al (Bioinformatics, 34(4), 2018, 660–668, in instant PTO-892), teach that there are key challenges for protein function prediction methods (see e.g. page 661, left column). These challenges arise from the difficulty identifying and accounting for the complex relationship between protein sequence structure and function (see e.g. page 661, left column). Despite significant progress in the past years in protein structure prediction, it still requires large efforts to predict protein structure with sufficient quality to be useful in function prediction (see e.g. page 661, left column). Another challenge is that proteins do not function in isolation. In particular higher level physiological functions that go beyond simple molecular interactions will require other proteins and cannot usually be predicted by considering a single protein in isolation (see e.g. page 661, left column). Due to these challenges it is not obvious what kinds of features should be used to predict the functions of a protein and whether they can be generated efficiently for a large number of proteins, such as the vast genus of proteins encompassed by the instant claims (see e.g. page 661, left column).
Given the teachings of these references that point out the limitations and pitfalls of using sequence to predict functions, and the lack of a representative number of species across the breadth of the genus, one of skill in the art would reasonably conclude that only the claimed 22-430 residues of SEQ ID NO: 66, but not the full breadth of the claims, meet the written description provision of 35 USC 112(a).
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the 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 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 from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, 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 the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 70-84 are rejected under 35 U.S.C. 103 as being unpatentable over Kumanogoh EP2497498 (IDS3/23/2023), Gu et al., 2002 (IDS3/23/2023) and Cerani et al., 2013 (IDS3/23/2023).
Kumanogoh teaches a method of administering agents to treat autoimmune diseases that are cause by an inflammatory response and include multiple sclerosis, uveitis and intraocular inflammation such as retinitis pigmentosa and macular edema (see paragraphs 3-7, 17-21 and 128) as in instant claim 81. Kumanogoh teaches that the inhibitor of binding between NRP1 and SEMA3A is useful for reducing inflammation (see paragraphs 15, 144 and abstract). Kumanogoh teaches producing a NRP1 that still retains Sema3a binding (see paragraph 16 section [10] (3)) but does not specifically teach using only the a1a2, b1 domains while excluding b2 and c domains. Kumanogoh teaches a polypeptide linker between NRP-1 and Fc (see paragraph 16 section [12] and paragraph 108) as in instant claims 70-74. Kumanogoh teaches that the agents include NRP-1 traps (see paragraphs 2, 16-18, 103-108) as in instant claims 70-74. Kumanogoh teaches SEQ ID NO: 2 (see page 38) which includes all of the required amino acids 22-430 of SEQ ID NO: 66. Kumanogoh teaches using a fusion protein that is NRP-1 FC fused at the amino terminal of NRP1 (see paragraphs 108, 113) as in instant claims 70-74. Kumanogoh teaches pharmaceutical compositions in liquid, aqueous form and injectable solutions and oral suspensions (see paragraphs 114-116) as in instant claims 75, 77-80. While Kumanogoh does not specifically teach ophthalmic pharmaceutical compositions of instant claim 76, one of ordinary skill in the art would be motivated to produce these pharmaceutical ophthalmic solutions since Kumanogoh teaches treating ocular diseases. One would want to administer the treatment directly to site it is required, the eye. While Kumanogoh teaches treatment that includes treating inflammation of the eye, Kumanogoh does not specifically teach the limitation of removing the required domains or specifically treating diabetic retinopathy or age-related macular degeneration as in instant claims 82-84.
Gu teaches that neuropilin-1 (Nrp-1 or Npn-1) is a receptor for both Sema3A and VEGF (see abstract). Gu teaches that the Npn-1 is the only receptor for Sema3A (see page 18069, 2nd column, 3rd paragraph). Gu teaches that the extracellular domain of Npn-1 contains two domains with homology to complement components C1r and C1s (CUB domains, also called “a1” and “a2”) at the amino terminus, followed by two coagulation factor V/VIII domains (CF V/VIII, also called “b1” and “b2”), and one C-terminal MAM domain (also called “c”; see page 18070, 1st column, 2nd paragraph). Gu teaches that each of the Npn-1 extracellular domains are required for biological activity mediated by Sema3A, but only the CUB domains (a1a2 domains) are required for binding to the same domain of Sema3A. Gu teaches that a Npn-1 variant lacking both a1 and a2 CUB domains is incapable of binding to Sema3A but does bind to VEGF (see page 18070, 1st column, 2nd paragraph) since b1, b2 and c domains are still present. These are the same domains as required in instant claim 70. Gu teaches that besides providing insights into the interaction of Npn-1 and its distinct ligands, Gu also provides a basis for rational drug design such as useful modulators or inhibitors of semaphorin/Nnp-1 signaling (see page 18070, 1st column, 2nd paragraph and page 18075, 1st column). Gu teaches that Sema3A and VEGF compete for the same receptor with different effects and one would want to keep these effects separate (see page 18075, 2nd column, 3rd paragraph). Gu’s teaching of the extracellular domains read on Nrp-1 polypeptide of instant claim 70. Gu does not explicitly teach soluble Nrp-1 with an FC.
Cerani teaches that deterioration of the inner blood-retinal barrier and consequent macular edema is a cardinal manifestation of diabetic retinopathy (DR) and the clinical feature most closely associated with loss of sight and that semaphorin 3A (SEMA3A) instigates pathological vascular permeability in diabetic retinas via its receptor neuropilin-1 (see abstract) as in instant claims 81-83. Cerani teaches that blocking NRP1, SEMA3A receptors, prevents retinal barrier functional breakdown (see page 511, bottom of 2nd column). Cerani teaches that anti-VEGF therapy attenuates neovascular age-related macular degeneration (AMD) and diabetic macular edema, has resulted in a profound change in clinical treatment paradigms, inhibition of a molecule that plays key roles in vascular homeostasis warrants contemplation these conditions where vascular stability is already compromised. Hence, neutralizing Sema3A instead of currently targeted factors such vasoprotective and neuroprotective VEGF and placental growth factor (PlGF) may provide a valid therapeutic alternative for diabetic retinopathy (see page 513, 2nd column, 3rd paragraph). Cerani does not specifically teach using the claimed fusion proteins to treat age-related macular degeneration or diabetic retinopathy.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosure of Kumanogoh, Gu and Cerani. The person of ordinary skill in the art would have been motivated to make and use the invention as claimed because Kumanogoh teaches treating inflammatory disease of the eye and one of ordinary skill in the art would be motivated to administer the agent as close as possible at the site of inflammation and injury, such as the eye, where the inflammation is occurring through routine optimization of the method (see MPEP § 2144.05). The person of ordinary skill in the art would have been motivated to make and use the invention as claimed because Nrp-1 is directly involved in Sema3A signaling, as taught by Kumanogoh. in view of Gu’s teaching that Sema3A needs the a1a2 domain of Nrp-1 for binding to occur. One of ordinary skill would be motivated to use a soluble NRP-1 and its fragment that consists of a1a2 domain to inhibit Sema3A ability to bind to the Nrp-1 receptors to prevent inflammation and treat diseases like age-related macular degeneration or diabetic retinopathy as taught by Cerani, and exclude the b2 and C domains since they are required for VEGF binding.
The person of ordinary skill in the art would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Conclusion
No claims are allowed.
Advisory Information
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.Any inquiry concerning this communication or earlier communications from the examiner should be directed to AURORA M. FONTAINHAS whose telephone number is 571-272-2952. The examiner can normally be reached on Monday - Friday (8AM - 4PM).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached on (571)272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675