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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-12 and species of SEQ ID NOs: 9-14, 15-19 and 19 in the reply filed on 2/17/20226 is acknowledged. Upon further consideration the restriction requirements are withdrawn.
Claims 1-14 are under consideration in the instant Office Action.
Information Disclosure Statement
The information disclosure statement filed 8/18/2023 fails to comply with 37 CFR 1.98(a)(3)(i) because it does not include a concise explanation of the relevance, as it is presently understood by the individual designated in 37 CFR 1.56(c) most knowledgeable about the content of the information, of each reference listed that is not in the English language and the citations have therefore been lined through. It has been placed in the application file, but the information referred to therein has not been considered.
Drawings / Sequence Compliance
The drawings are objected to because this application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR § 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR § 1.821 through 1.825 for the following reasons: Figure 2c contains sequences that are not properly identified in the instant Figure 2c description in the instant specification. Note that (a) 37 CFR § 1.821(a) states that an unbranched sequence of four or more amino acids or an unbranched sequence of ten or more nucleotides requires a sequence identifier. In case these sequences are not in the current "Sequence Listing,” applicant must provide a substitute computer readable form (CRF) copy of a Sequence Listing which includes all of the sequences that are present in the instant application and encompassed by these rules, a substitute paper copy of that Sequence Listing, an amendment directing the entry of that paper copy into the specification, and a statement that the content of the paper and computer readable copies are the same and, where applicable, include no new matter, as required by 37 C.F.R. §§ 1.821(e) or 1.821(f) or 1.821(g) or 1.825(b) or 1.825(d). The instant specification will also need to be amended so that it complies with 37 C.F.R. § 1.821(d) which requires a reference to a particular sequence identifier (SEQ ID NO:) be made in the specification wherever a reference is made to that sequence.
Nucleotide and/or Amino Acid Sequence Disclosures
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawing, Figure 2C, are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification, see page 26, Table 4, are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
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 3-4 and 12-13 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.
Instant claims 3-4 and 13 recite epitopes and the CDRs and heavy chain variable region sequences of the claimed antibody as “… an amino acid sequence having a sequence identity…” It is unclear what is meant by “an amino acid sequence having a sequence identity” as the use of “an amino acid” broadens the scope of the claim as it does not explicitly define all embodiments of the sequence. For example, this terminology of “an amino acid” can be interpreted as a subset of amino acids contained within the listed sequence identity number. Applicant is encouraged to amend the claim language to read as “…comprising SEQ ID NO:…” or “…comprising the amino acid sequence of SEQ ID NO:…” at every iteration to obviate this rejection.
Further, claims 3-4 and 13 use the transitional term “having”. This term is problematic because it is not immediately clear whether open or closed claim language is intended, Crystal Semiconductor Corp. v. TriTech Microelectronics Int’l Inc., 246 F.3d 1336, 1348, 57 USPQ2d 1953, 1959 (Fed. Cir. 2001) (term “having” in transitional phrase "does not create a presumption that the body of the claim is open"); Regents of the Univ. of Cal. v. Eli Lilly & Co., 119 F.3d 1559, 1573, 43 USPQ2d 1398, 1410 (Fed. Cir. 1997) (in the context of a cDNA having a sequence coding for human PI, the term “having” still permitted inclusion of other moieties), see MPEP 2111.03. Applicant is encouraged to use transitional phrases “comprising of” or “consisting of” to define the scope of a claim with respect to what unrecited additional components, if any, are excluded from the scope of the claims.
MPEP § 2173.02 (II) states that one of the purposes of examination under 35 USC § 112, second paragraph is to determine whether the claim apprises one of ordinary skill in the art of its scope and, therefore, serves the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent. See, e.g., Solomon v. Kimberly-Clark Corp., 216 F.3d 1372, 1379, 55 USPQ2d 1279, 1283 (Fed. Cir. 2000). See also In re Larsen, No. 01-1092 (Fed. Cir. May 9, 2001) (unpublished). If the language of the claim is such that a person of ordinary skill in the art could not interpret the metes and bounds of the claim so as to understand how to avoid infringement, a rejection of the claim under 35 U.S.C. 112, second paragraph, would be appropriate. See Morton Int’l, Inc. v. Cardinal Chem. Co., 5 F.3d 1464, 1470, 28 USPQ2d 1190, 1195 (Fed. Cir. 1993). In this case, others are not fairly apprised of the scope of the claimed sequences for the claimed epitopes and CDRs and heavy chains of the claimed antibodies and thus not fairly warned as to what constitutes infringement.
Claim 12 is found indefinite since it is unclear how a product composition has a subject with an intraocular pressure of 10 to 21 mm Hg. This claim appears to be towards a method rather than a product limitation. It is unclear what this limitation’s purpose is for. Canceling claim 12 would overcome this rejection over claim 12.
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 1-14 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.
See MPEP §2163(I)(A) which states: "The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art recognized correlation or relationship between the structure of the invention and its function. A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.”
The claims are drawn quite broadly to an optic nerve protecting agent that requires a generic anti-LRP-1 antibody. The independent claim is not limited by a structure or particular protein, DNA, RNA or chemical required for the agent. While the agent is limited to a function of specifically binding LRP-1. Claim 2 only sets forth epitopes that their claimed antibody may bind but again fails to set forth any specific structure for the claimed antibody. Only dependent claim 4 and independent claim 13 further limit the agent to anti-LRP-1 antibodies with amino acid variable structure that encompassed antibodies that have CDR sequences with up to 20% differences from the instant sequences set forth, there is no specific structure that is required beyond the generic form of an antibody.
Further, one of the genus that is encompassed by the claimed agent is the anti-LRP-1 antibodies which are claimed by what they bind, as in instant claims 2-3, without any further required structure. By claiming an antibody through its function, it fails the written description because there is no specific structure to describe the claimed antibody since an antibody that binds LRP-1 does not require any specific structure be maintained beyond maintaining its function. The instant specification fails to provide written description support for the instantly claimed antibody agent because while the instant specification only teaches the possible epitopes it might bind it does not provide any specific antibodies beyond the one disclosed antibody in the instant specification and does not teach any other specific structures, like CDRs, of other possible antibodies. There is no written description support for the claimed agents, even if limited to antibodies, in the instant specification since these claims are not limited to any specific antibody structure. This reads on a claimed genus of antibodies that does not have written description support in the instant specification since they are described by their function and epitope but provide no specific structure except for the specifically disclosed antibody to embody the genus of antibodies that they are claiming.
The instant invention is claiming an optic nerve protecting agent comprising an antibody that binds to LRP-1 to provide optic nerve protection. Independent claim 13 and dependent claim 4 call out an anti-LRP-1 antibody with modifiable CDR sequences that allows up to 20% differences in the amino acids sequences. Dependent claim 5, which depends from independent claim 1 encompasses a human antibody. There is no description of the structure of any human antibodies. Thus to the extent that the claims encompass human antibodies, they fail to meet the written description rejection.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Vas-Cath, Inc., v. Mahurkar, 935 F.2d at 1563, 19 U.S.P.Q.2d at 1116.
In the instant case, there is no corresponding progression exists with respect to making a fully-human antibody (comparing the process of constructing a chimeric antibody from a mouse antibody with the process of making a human antibody). One of skill in the art cannot look at a mouse variable region and know how to turn it into a human variable region with the same affinity and activity as the mouse antibody.
Applicant has not described the claimed invention sufficiently to show they had possession of the claimed genus of anti-LRP-1 antibodies or human antibodies. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester v. G.D. Searle & Co., 358 F.3d 916, 69 USPQ2d 1886 (Fed. Cir. 2004).
In this case, antibodies generally share certain characteristics such as Fc regions or hinge regions. However, these structures are not correlated with the binding function of the antibody. The hyper variable regions (HVRs), i.e., complementarity determining regions (CDRs) of an antibody, are well established in the art as the portion of the binding region which imparts the specificity of an antibody. However, there is no way to a priori look at an epitope and envisage the combination of six CDRs that will bind that antigen. First, even highly related CDRs may not bind the same target. See for example Kussie et al., 1994 (instant PTO-892) who demonstrates that a single amino acid change in the heavy chain of an antibody which binds p-axophenylarsonate (Ars) completely abrogates the ability of the antibody to bind Ars but adds the functionality of binding the structurally related p-azophenylsulfonate (e.g., abstract). Second, even when provided with several related antibodies that bind the desired target, this does not represent the astronomical and potentially unknowable breadth of all possible amino acid sequences which will result in the desired binding properties. This is exemplified by the Court decision in Abbvie (Abbvie v Janssen 759 F.3d 1285 (Fed. Cir. 2014)), where Abbvie developed over 200 antibodies that shared 99.5% identity in the variable regions (p.7) and which bound the target, but in no way allowed one to envisage the unique structure of Centocor’s antibodies which bound the same target but shared only 50% sequence similarity (see table on page 11).
Thus, the art recognizes that the CDRs define the binding properties of an antibody and that even single amino acid changes to this region can completely abrogate the binding specificity of an antibody. As a further example, see Chen et al., 1995 (instant PTO-892) which demonstrates single amino acid changes in the VH CDR2 sequence can increase binding, decrease binding, destroy binding, or have no effect on binding when compared to the wild-type antibody.
The instant specification discloses one antibody in the instant specification. However, as discussed above, without any way to determine how broad the genus of such antibodies are, there is no way to determine if these antibodies represent the full breadth of what is claimed. The disclosure of these specific antibodies would not convey to the artisan that Applicant was in possession of the full genus of all antibodies which possess the required functions required to treat or prevent any inflammatory disease nor does it allow the skilled artisan to envisage the specific structure of such antibodies.
Instant claims 4 and 13 recite heavy and light chain variable region sequences and CDRs with 80% identity to the VH and VL sequences and CDRs. Applicant has not demonstrated that they are in possession of all the molecules that fall within the immense scope of the claim that are able to achieve the claimed function.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Vas-Cath, Inc., v. Mahurkar, 935 F.2d at 1563, 19 U.S.P.Q.2d at 1116. The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function. An antibody described only by functional characteristic, such as antibody that binds to LRP1 and specific epitope of instant claim 3, without any known or disclosed correlation between that function and the structure of the sequence, is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the biomolecule of interest. In re Bell, 991 F.2d 781, 26 U.S.P.Q.2d 1529 (Fed. Cir. 1993). In re Deuel, 51 F.3d 1552, 34 U.S.P.Q.2d 1210 (Fed. Cir. 1995). In the instant case, the specification provides insufficient direction or guidance concerning the relationship between the structure of the possible antibody to demonstrate possession of the breadth of the genus of LRP-1 antibodies encompassed by the instant claims, especially in view of the unpredictability of such an endeavor. The prior art as evidenced by Edwards et al., 2003 (instant PTO-892) teaches there is a substantially huge antibody diversity produced to one single antigen target. Edwards provides evidence that over 1000 antibodies, all different amino acid sequences, were generated towards one single protein antigen target (see abstract). Without a correlation between structure and function, the claims do little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
Without this guidance or direction the skilled artisan would not consider applicant to be in possession of the claimed genus of antibodies because the skilled artisan recognizes that even seemingly minor changes made without guidance or direction as to the relationship between the particular amino acid sequence of the instantly claimed antibody and its ability to bind antigen, can dramatically affect antigen-antibody binding.
Applicant has not described the claimed invention sufficiently to show they had possession of the claimed genus of antibodies that binds to LRP-1. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester v. G.D. Searle & Co., 358 F.3d 916, 69 USPQ2d 1886 (Fed. Cir. 2004).
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. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. What constitutes a "representative number" is an inverse function of the skill and knowledge in the art. Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved since there is no disclosure of the specifically claimed antibodies that bind CTGF. The instant specification only discloses one specific antibody. Therefore, the instant specification only provides a possible antibody of the claimed genus of possible antibody agents. There are no other examples in the instant specification that support all of the other possible antibodies with the required function.
Further, see MPEP 2163 II A 3(a) which states “disclosure of an antigen fully characterized by its structure, formula, chemical name, physical properties, or deposit in a public depository provides an adequate written description of an antibody claimed by its binding affinity to that antigen, if "generating the claimed antibody is so routine that possessing the [antigen] places the applicant in possession of an antibody." Centocor or Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1351-52, 97 USPQ2d 1870, 1877 (Fed. Cir. 2011), distinguishing Noelle v. Lederman, 355 F.3d 1343, 1349, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (holding there is a lack of written descriptive support for an unknown antibody defined by its binding affinity to an antigen that itself was not adequately described). Centocor or concerned claims to antibodies with specific properties, including high affinity to a particular antigen, which was characterized in the prior art. The patent disclosed the antigen, but did not disclose any antibodies with the specific claimed properties. The court held that the claimed antibodies were not adequately described because the generation of such antibodies was not possible using conventional, routine or well-developed technology as of the priority date of the patent.”
The same fact pattern is found in the instant case since the claims and instant specification only claim antibodies by their antigen protein and only disclose an antibody to encompass the genus with very specific function requirements, let alone antibodies that are capable of binding to LRP-1.
Finally, note the decision in Amgen v. Sanofi 2017, where the Court supported previous decisions (Centocor 2011; Abbvie 2014) that defining an antibody solely by what it binds does not satisfy the written description requirement, stating that this would allow patentees to “claim antibodies by describing something that is not the invention, i.e., the antigen”.
Applicant has not described the claimed invention sufficiently to show they had possession of the claimed agents and one of the genus that encompasses the claimed antibodies. Here, applicants have not described a reasonable number of members of the genus of compounds that have the functional requirements of the claims, i.e. the required as starting materials for the claimed methods since they have not establish an adequate structure/function correlation for the claimed antibodies.
With the exception of the specifically disclosed antibodies in the instant specification, the skilled artisan cannot envision these agents or the antibodies, and therefore conception is not achieved until reduction to practice has occurred, 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 of isolating it. The product itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF's were found to be unpatentable due to lack of written description for that broad class. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
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 and 7-11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sanchez et al, 2006 (instant PTO-892).
The instant claim 1 requires an anti-LRP1 antibody.
Sanchez teaches that LRP1 is linked to retinal neovascularization (see abstract) and linked to glaucoma (see page 1383, 2nd column, middle of 3rd paragraph) and reads on instant claims 1 and 7-11. Sanchez teaches anti-LRP1 antibodies (see page 1380, 2.4 Immunohistochemistry). There is no evidence that these antibodies are not capable of being used as intended and capable of producing the intended results. It has been held that a recitation with respect to the manner in which a claimed composition is intended to be employed, treating ocular diseases, as in instant claims 1 and 7-11, does not differentiate the claimed composition from a prior art composition satisfying the claimed structural limitations. Ex parte Masham, 2 USPQ2d 1647 (1987). MPEP 2112.02 states when the claim recites using an old composition or structure and the "use" is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978) (Claims 1 and 6, directed to a method of effecting nonaddictive analgesia (pain reduction) in animals, were found to be anticipated by the applied prior art which disclosed the same compounds for effecting analgesia but which was silent as to addiction. The court upheld the rejection and stated that the applicants had merely found a new property of the compound and such a discovery did not constitute a new use. The court went on to reverse the obviousness rejection of claims 2-5 and 7-10 which recited a process of using a new compound. The court relied on evidence showing that the nonaddictive property of the new compound was unexpected.). See also In re Tomlinson, 363 F.2d 928, 150 USPQ 623. "While the references do not show a specific recognition of that result, its discovery by appellants is tantamount only to finding a property in the old composition." 363 F.2d at 934, 150 USPQ at 628 (emphasis in original)).
Conclusion
No claims are allowed.
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/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675