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 .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The present application is drawn from PCT/US2022/037704, filed 7/20/2022; and claims benefit under 35 U.S.C. 119(e) to U.S. Provisional application 63/224214, filed 7/21/2021.
Status of Claims
Claims 1-3, 5-15 and 24-29 are pending and are being examined on the merits.
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 1-2, 5 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Hageman (from IDS of 1/19/2024; WO 95/17673; published 6/29/1995) and Shin et al., (from IDS of 1/19/2024; Science Advances, 9/11/2019).
Hageman teaches methods for treating age-related macular degeneration (AMD) based on targeting vitronectin (abstract). Hageman teaches that AMD is manifested by abnormal deposition of material in the vascular bed in the macular region, some deposits are drusen (pg. 2, lines 20-30). Hageman teaches the invention identifies vitronectin as a principle molecular constituent of drusen and other abnormal deposits associated with AMD and specific agents for blocking the deposition of vitronectin (pg. 4, lines 1-7). Specifically, Hageman teaches compounds which act by binding potential components of deposits and inhibiting their ability to participate in the molecular interactions necessary to form a relatively insoluble deposit (pg. 23, lines 27-31). Thus, Hageman teaches anti-vitronectin antibodies are contemplated for use in the invention, as well as “any peptide specific for vitronectin or a fragment of vitronectin,” (pg. 15, lines 1-5). Hageman teaches numerous compounds which bind to vitronectin (pg. 22, lines 14-35; Table 1). Hageman teaches AMD is the primary target for diagnosis and treatment using the invention (pg. 26, lines 8-9), whereby the most preferable tissue is human ocular tissue (pg. 25, lines 16-17), and includes a slow release delivery of an “opthlamic composition to the eye,” (pg. 28 lines 34-38), or an intraocular administration (pg. 29, lines 9-12).
Thus, Hageman teaches a methods of ameliorating an extracellular accumulation of vitronectin by administering a vitronectin-ameliorative compound, in ocular tissue, whereby the compound is an anti-vitronectin antibody (or an anti-vitronectin peptide); as well as an ocular composition comprising the anti-vitronectin compound (pgs. 53-55; claims 1, 3, 7 and 28-29).
However, Hageman does not teach wherein the anti-vitronectin compound inhibits the activity of a hydroxyapatite binding site of vitronectin, or wherein the binding site is an HX domain of vitronectin.
Shin (2019) teaches the structure of human vitronectin and its interactions. Shin teaches vitronectin comprises 4 HX domains, HX1, HX2, HX3 and HX4, with a representation of the vitronectin polypeptide delineating the residues of each HX domain (see pg. 2, Fig. 1, pg. 4, Fig. 2). Shin discloses 3 antibodies were probed for binding to vitronectin (Vn) or a purified Vn-Hx, which starts at Glu154 of HX1 (pg. 5, Fig. 3). Shin used 3 antibodies; Abn, which binds residues 141-154 (not HX), ABm, which binds residues 209-258 (HX2); and ABc, which binds residues 446-472 (HX4). Shin discloses that antibody Abn does not bind the Vn-HX molecule, as it is directed to residues before the HX domains, which are not included in the Vn-HX construct. Conversely, antibodies Abm and Abc do bind Vn-HX and map to HX2 and HX4, respectively (Fig. 3). Note that the antibodies Abn, Abn and Abc of Shin (2019) are the same antibodies described in the instant specifications (pg. 9, para. 0066), whereby antibody Abm inhibits Vn-dependent hydroxyapatite deposition.
It would have been obvious to one of skill in the art to use the anti-vitronectin antibody Abn, of Shin et al., in the ophthalmic methods and compositions of Hageman et al. One would have been motivated to do so given that anti-vitronectin antibodies inhibit the vitronectin-mediated accumulation of drusen, as a means of ameliorating macular degeneration, as taught by Hageman et al. There would have been a reasonable expectation for success given that vitronectin is a principle molecular constituent of drusen and other abnormal deposits associated with AMD, and anti-vitronectin antibodies inhibit the deposition of vitronectin, as taught by Hageman; and that antibody Abn binds an hydroxyapatite-binding HX domain of vitronectin, as taught by Shin et al. Thus, the invention was prima facie obvious to one of skill in the art at the time the invention was made.
Regarding claim 1; as the instant specifications disclose antibody Abn inhibits hydroxyapatite binding by vitronectin, by binding to an HX domain, as taught by Shin, it is an inherent property of the antibody Abn to inhibit the activity of a calcium and hydroxyapatite binding site of vitronectin. Thus, the combination methods of Hageman and Shin make obvious the methods of instant claim 1.
Regarding claims 2 and 9; Hageman teaches the anti-vitronectin antibody for treating macular degeneration due to the accumulation of drusen deposits, whereby vitronectin is a principle constituent of drusen, and whereby the accumulation occurs in ocular tissue, or more specifically “in the eyes of human patients with AMD,” (pg. 4, lines 3-5). As the methods of Hageman target treating age-related macular degeneration by targeting vitronectin in the human eye, the combination of Hageman and Shin make obvious instant claims 2 and 9.
Regarding claim 5; Hageman teaches the composition of the invention includes a therapeutic compound which may be formulated with small amounts of adjuvants such as buffers and preservatives to maintain isotonicity, physiological and pH stability (pg. 27, lines 32-35). Thus, the combination of Hageman and Shin make obvious instant claim 5.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Hageman (from IDS of 1/19/2024; WO 95/17673; published 6/29/1995) and Shin et al., (from IDS of 1/19/2024; Science Advances, 9/11/2019) as applied to claims 1-2, 5 and 9 above, and further in view of Sugrue et al., (from IDS; US Patent 5,900,414; issued 5/4/1999).
The reasons why the combination of Hageman and Shin make obvious instant claims 1-2, 5 and 9 is described above. Specifically, Hageman and Shin make obvious a method of inhibiting vitronectin activity by administering an anti-vitronectin antibody composition for the purpose of ameliorating the vitronectin/drusen deposit accumulation as a means for treating macular degeneration.
However, neither Hageman or Shin teaches wherein the composition further comprises a thickening agent which is gellan gum or xanthan gum.
Sugrue et al. teaches compositions and methods for systemically administering agents in an ophthalmic formulation, to the patient’s eye (abstract). Sugrue teaches the agents may be a vitronectin receptor antagonist (col. 1, lines 13-15); and may be used for inhibiting macular degeneration (col. 4, lines 20-22). Sugrue teaches the preparations may be solutions, suspensions, inserts or ointments (col. 3, lines 63-65). Sugrue teaches administration may include an ophthalmic solid insert which, after dispensing the active agent, remains essentially intact or bio-erodes; and that the polymer used to form the insert may be any water-soluble non-toxic polymer, such as gellan gum and xanthan gum (col. 5, lines 17-35).
It would have been obvious to one of skill in the art to modify the ophthalmic composition of the combination of Hageman and Shin to be an ophthalmic insert comprising xanthan gum. One would have been motivated to do so in order to provide an alternative means of administering an agent for treating macular degeneration to the ocular tissue. There would have been a reasonable expectation for success given that gellan gum or xanthan gum are suitable polymers for generating an ophthalmic insert, as taught by Sugrue et al. Thus, the invention was prima facie obvious to one of skill in the art at the time the inventio was made.
Regarding claim 6; the combination of Hageman, Shin and Sugrue make obvious formulating an ophthalmic composition comprising an anti-vitronectin antibody as an ocular insert, whereby the insert comprises a thickening agent which is gellan gum or xanthan gum. Thus the combination of Hageman, Shin and Sugrue make obvious instant claim 6.
Claim Rejections - 35 USC § 112(a)
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 3, 7-8, 10-15, and 24-29 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.
The following quotation from section 2163 of the Manual of Patent Examination
Procedure is a brief discussion of what is required in a specification to satisfy the 35 U.S.C. 112 written description requirements for a generic claim covering several distinct inventions:
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 Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
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.
Thus, when a claim covers a genus of inventions, the specification must provide written description support for the entire scope of the genus. Support for a genus is generally found where the applicant has provided a number of examples sufficient so that one in the art would
recognize from the specification the scope of what is being claimed.
Claims 3, 10 and 24 recite wherein the composition comprises an organic compound which inhibits vitronectin binding to calcium or hydroxyapatite, and wherein the organic compound is less than 1,000 Daltons. Thus, the claims are interpreted to encompass a genus of small molecule and peptide structures that are < 1 kDa and bind vitronectin to inhibit the calcium and hydroxyapatite binding domains, whereby the structure of the compounds/peptides are unidentified.
In support of the claimed genus, the specifications do not recite a single example of a molecule or peptide which meets the claim limitations. The specifications describe the functionality via use of 3 known anti-vitronectin antibodies (pg. 9, para. 0066). However, it is known that antibodies are approximately 150 kDa, and even the smallest antigen binding domain of antibodies (i.e. an scFv) is approximately 25 kDa. Thus, by limiting the size of the organic molecule to less than 1 kDa, the claims are essentially excluding any type of antibody or fragment thereof. The specifications teach an in vitro assay, using a proto-spherule like those found in drusen deposits of AMD, “was used to discover inhibitors”, (pg. 7, para. 0051). However, no mention of a single example of the “discovered inhibitors” is provided. The specifications recite “suitable inhibitors of the HX domain of Vn can be identified by screens,” (para. 0052). However, again, no examples of any “identified inhibitors” are provided. It is not clear if the inhibitors are intended to be peptides or small molecule drugs. It is unclear if the inhibitors are naturally occurring, whereby they are isolated from humans, or if they are intended to be synthetically derived chemical compounds. The examples describe the assessment of Vn in binding hydroxyapatite (HAP), but do not describe any compounds which inhibit the binding; the example teaches amyloid-β has no effect on mineralization and pyrophosphate (PPi) is a mineralization inhibitor which serves as a negative control (pg. 9, para. 0065; Fig. 1). Applicants only show the antibodies as proof of principle (pg. 9, para. 0066; Fig. 2). The specifications have a section heading “Inhibitory Activities” only to be followed by the single statement, “the inhibitory activities of the optimized compounds are measured.” The next section heading is “Ophthalmic Compositions”; only to be followed by a single statement, “ophthalmic compositions containing an effective amount of the optimized compounds are prepared and tested,” (pg. 9, paras. 0067-0071). The lack of even a single described example of an identified compound which is <1kDa in size and inhibits vitronectin binding to HAP is striking.
When determining the representative examples and the art, it is important to consider whether there is evidence of a singular shared structural feature which imparts the defining property of the claimed genus, and which would necessarily be present in every species of the claimed genus. In this case, no compounds or peptides which meet the claims limitations are embodied, thus there can be no inference of any shared structural features across embodiments.
It is known in the art that a binding entity must have certain structural, physical or chemical elements which impart its specificity and affinity for its target. For example, the antigen binding domain of an antibody requires the 6 complementarity determining regions (CDR) of the heavy and light chains, whereby the 3 CDRs of the heavy chain and the 3 CDRs of the light chain are structurally inter-dependent in forming the unique binding pocket of the antibody paratope region; and thus the CDRs constitute critical aspects of the antibody paratope and ultimately impart the paratope-epitope binding functionality with regard to specificity and affinity (for review see MacCallum et al., 1996). Thus, for an organic compound to inhibit the activity of a calcium and hydroxyapatite binding site of vitronectin, or wherein the binding site is an HX domain, the compound must have a specificity to a target structure on vitronectin; and that specificity is imparted by the amino acid resides or chemical features of the compound which differentiate it from a compound binding, for example α-synuclein. Hageman et al. (from IDS; WO 95/17673) teaches a number of proteins which bind to vitronectin, generally (see Table 1); however, each of these proteins would be well over 1 kDa in size and may bind any part of vitronectin. As the instantly claimed compounds bind a specific region (i.e. an HX domain) of vitronectin, and are < 1kDa in size, it should be clear that they have a minimum structural basis which imparts the function. Regarding the size, the specifications recite “1,000 Daltons” 6 times. In each case it simply states that embodiment include organic compounds having a molecular weight of less than 1,000 Da. There is no description of example compounds or their size. That is, the specifications do not teach any technological advantage to the compound being < 1 kDa in size, versus for example, the proteins which bind vitronectin of Hageman (Table 1). Why is it necessary that they be less than 1,000 Da in size?
Section 2163(II)(A)(3)(a)(ii) of the MPEP states that the written description for a claimed genus may be satisfied through either a) a representative number of species, or b) disclosed correlation between function and structure. Here the applicants do not provide any examples of the claimed embodiments; nor do they identify any shared structural properties of the alternative species of the claimed genes. It is not even clear if the compounds are small peptides or small molecule drugs. Currently the essential property of binding an HX domain of vitronectin is imparted by the 3 antibody species tested, yet antibodies and functional antibody fragments are excluded from the invention by way of requiring the compounds to be < 1 kDa in size. Thus, the claims encompass a genus of compounds, yet the examples do not provide a single species of the claimed genus, nor any description of structure-to-function relationship of any of the species of the claimed genus. Specifically, the physical features (or amino acid residues encoding said features) which impart the property of binding the same epitope of vitronectin, whereby the activity of the HAP binding site is inhibited, should be disclosed. This lack of definition complicates the determination of the boundaries of the claimed genus with regard to which, as of yet unidentified, species variants would be anticipated, a priori, by one skilled in the art, to fall within the scope of the claims.
The specification describes an in vitro assay, whereby “suitable inhibitors of the HX domain of Vn can be identified by screens” whereby “compounds which exhibit high therapeutic indices are preferred,” (pg. 7; paras. 0052 and 0056). These are desired properties of the compounds, but no description is provided as to the structure of the embodiments that result from the screening. The specifications appear to suggest the skilled artisan must invent the invention; whereby the artisan is tasked to screen, discover and isolate compounds which bind the target, and are < 1 kDa in size, and then formulate a therapeutically effective amount of the unknown compound in a composition. The labor of inventing is taking an idea and turning it into a novel and practical application/product. Here the specifications seem to describe a concept of an invention, without a corresponding reduction to practice of a single embodiment. While the suggested screening process might enable the artisan to practice the invention, it does not provide descriptive support sufficient to determine the applicants had possession of the invention.
“The purpose of the written description requirement is to ‘ensure that the scope of the
right to exclude, as set forth in the claims, does not over-reach the scope of the inventor’s
contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli
Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D.
Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description
requirement, the 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. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir.
1991). See also MPEP 2163.04. Otherwise, the “claims merely recite a description of the
problem to be solved while claiming all solutions to it and … cover any compound later actually
invented and determined to fall within the claim’s functional boundaries- leaving it to the
pharmaceutical industry to complete an unfinished invention.” Ariad Pharmaceuticals, Inc. v. Eli
Lilly and Co., 598 F.3d 1336, 1353 (Fed. Cir. 2010).
Applicants have not described a single embodiment of a compound which inhibits the HAP binding site of vitronectin, and which is < 1 kDa in size, for use in an ophthalmic composition. Applicants provide no description of any technological advantage of a compound being < 1 kDa over alternative anti-vitronectin binding compounds, such as antibodies, that are known in the art. The applicants have failed to show that they have possession of any species of the claimed genus of organic compounds. Thus, claims 3, 10 and 24 are rejected for lack of adequate descriptive support. As claims 7-8, 11-15 and 25-29 depend from claims 3, 10 or 24, but fail to rectify the deficient descriptive support issues, they are also rejected.
Conclusion
No claims are allowed.
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/JAMES RYLAND MELCHIOR/Examiner, Art Unit 1644
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642
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