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 .
Election/Restriction
The response filed on 4/24/26 to the restriction requirement of 2/6/26 has been received. Without traverse, Applicant has elected SEQ ID NO:34.
Claims 1, 26, 27, 30-32, 37-41, 59, 63, 67, 71, 72, 74, 82-84, 87, 95, 96, 99, 100, and 118 are pending.
Claims 30, 37, and 71 are withdrawn from further consideration by the examiner under 37 CFR 1.142(b) as being drawn to a non-elected invention.
Claims 1, 26, 27, 31, 32, 38-41, 59, 63, 67, 72, 74, 82-84, 87, 95, 96, 99, 100, and 118 are currently under consideration.
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 32, 39-41, 59, 63, 67, 72, 74, 82-84, 87, 95, and 96 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.
Claim 32 is rejected for reciting “The protein of claim 1…are the same as those found at the corresponding position in a protein selected from the group consisting of…with the proviso that the protein may comprise a….” It is unclear which position of each protein of the Markush group is “the corresponding position.” Noting claim 32 claims a protein and recites numerous proteins in a Markush group, there is insufficient antecedent basis for “the protein” at the second to last line of the claim.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 39 recites the broad recitation that "each X independently represents any amino acid", and the claim also recites X at position 16 is D or E, X at position 37 is E or Q, X at position 24 is Y and/or X at position 42 is W - which is the narrower statement of the range/limitation. Therefore claims 39-41, 59, 63, 67, and 72 are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 74 recites “…wherein the amino acid sequence….” There is insufficient antecedent basis for “the amino acid sequence” in the claim.
Claim 82 contains the trademark/trade name “nanobody”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe an antibody fragment and, accordingly, the identification/description is indefinite. Further, it is unclear how or if the text after “e.g.” limits the claim. Therefore, claims 82-84, 87, 95, and 96 are rejected.
Claim 95 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, because 35 U.S.C. 112(b) and 35 U.S.C. 112 (pre-AIA ), second paragraph, require claims to particularly point-out and distinctly claim subject matter. The instant claim attempts to incorporate by reference to a specific table or figure; however, such incorporation is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. In the instant case, there is a practical way to define the invention in words. Incorporation by reference is a necessity doctrine, not for applicant’s convenience. See MPEP 2173.05(s).
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, 26, 27, 31, 32, 38-41, 59, 63, 67, 72, 74, 82-84, 87, 95, 96, 99, 100, and 118 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for making and using proteins comprising a C3 or C3b binding polypeptide comprising SEQ ID NOs: 27, 33, or 34 (see Example 5, in particular), does not reasonably provide enablement for making or using proteins comprising a C3 or C3b binding polypeptide comprising instant SEQ ID NO:22, 23, 24, 65, or 77 wherein the X positions of SEQ ID NO:22, 23, 24, 65, and 77 are those permitted by the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required are summarized in Ex parte Forman, 230 USPQ 546 (BPAI 1986). They include the nature of the invention, the state of the prior art, the relative skill of those in the art, the amount of direction or guidance disclosed in the specification, the presence or absence of working examples, the predictability or unpredictability of the art, the breadth of the claims, and the quantity of experimentation which would be required in order to practice the invention as claimed.
The instant claims are drawn to proteins comprising a C3 or C3b binding polypeptide comprising instant SEQ ID NO:22, 23, 24, 65, or 77 wherein the X positions of SEQ ID NO:22, 23, 24, 65, and 77 are those permitted by the claims. This includes proteins that have yet to be shown to be capable of binding C3 or C3b. SEQ ID NO:77, for example has the following sequence:
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346
586
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Instant claim 1 limits a C3 and/or C3b binding protein to comprise amino acids 2-60 of SEQ ID NO:77 wherein X at positions 2, 3, 4, 6, 15, 18, 31, 37-39, 57-59, and 61-68 are as set forth below:
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591
722
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and wherein SEQ ID N:77 comprises Y at position 25, W at position 44, and at least one of the following:
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374
341
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The genus of proteins having an amino acid sequence permitted by the claim that has the function of binding C3 or C3b has not been adequately described.
This invention is in a class of invention which the CAFC has characterized as "the unpredictable arts such as chemistry and biology". Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
In regards to claims to a product defined by function, without a correlation between structure and function, the claim does little more than define the claimed invention by function. See Eli Lilly, 119 at1568 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”).
The specification discloses, and the prior art teaches, C3 or C3b binding polypeptides (see Abstract of US 2019/0322730 A1; 10/24/19) and Example 5 of the instant specification). However, neither the specification nor the prior art adequately describes the claimed genus. Only three members of the genus have been described (SEQ ID NOs: 27, 33, and 34). Undue experimentation, which would require generating and screening polypeptides, would be required to identify the genus as broadly claimed.
Further, in regards to a genus encompassing variants characterized by having an activity, structural features that distinguish the genus from others not encompassed by the genus are missing from the disclosure. No common structural attributes identify the members of the genus. The general knowledge and level of skill in the art do not supplement the omitted description because specific, not general, guidance is needed. In the instant case, there is not teaching as to which combinations of amino acids for each “X” would, or would not, result sin C3 or C3b binding. General knowledge in the art includes knowledge that some amino acid variations are tolerated without losing a protein’s structure; however, those of skill in the art would recognize that conservation of structure is not necessarily a surrogate for conservation of function. For example, Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) shows that a conservative replacement of a single “lysine” residue at position 118 of acidic fibroblast growth factor by “glutamic acid” led to a substantial loss of heparin binding, receptor binding and biological activity of the protein. Similarly, Lazar et al. ( Mol. Cell Biol. 8:1247-1252, 1988) teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 alone with alanine or asparagines 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 or what appears to be an inconsequential chemical modification will often dramatically affect the biological activity and characteristics of a protein.
One cannot extrapolate the teachings of the specification to the scope of the claims because the claims are broadly drawn to proteins comprising a C3 or C3b binding polypeptide comprising instant SEQ ID NO:22, 23, 24, 65, or 77 wherein the X positions of SEQ ID NO:22, 23, 24, 65, and 77 are those permitted by the claims, and Applicant has not enabled said method because the genus of proteins comprising a C3 or C3b binding polypeptide comprising instant SEQ ID NO:22, 23, 24, 65, or 77 wherein the X positions of SEQ ID NO:22, 23, 24, 65, and 77 are those permitted by the claims have not been adequately described and it would require undue experimentation to adequately describe the genus of polypeptides encompassed by the claims.
In view of the teachings above and the lack of guidance, workable examples and or exemplification in the specification, it would require undue experimentation by one of skill in the art to make or use the recited polypeptides.
Further, similar to claims at issue in Amgen Inc. v Sanofi, the instant specification does not enable the full scope of the claims. The instant specification, in view of the prior art, does not teach one of skill the recited genus of a C3 or C3b binding polypeptides comprising instant SEQ ID NO:22, 23, 24, 65, or 77 wherein the X positions of SEQ ID NO:22, 23, 24, 65, and 77 are those permitted by the claims.
Claim Rejections - 35 USC § 112
Claims 1, 26, 27, 31, 32, 38-41, 59, 63, 67, 72, 74, 82-84, 87, 95, 96, 99, 100, and 118 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. In the instant case, the claims are inclusive of a genus of C3 and C3b binding polypeptides comprising instant SEQ ID NO:22, 23, 24, 65, or 77 wherein the X positions of SEQ ID NO:22, 23, 24, 65, and 77 are those permitted by the claims. However, the written description in this case only sets forth polypeptides comprising SEQ ID NOs: 27, 33, or 34. The specification does not disclose, and the art does not teach, the genus as broadly encompassed in the claims.
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or by describing structural features common to that genus that “constitute a substantial portion of the genus.” See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997): “A description of a genus of cDNAs may be achieved by means of a recitation of a representative number of cDNA, defined by nucleotide sequence, falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus.”
The inventions at issue in Lilly were DNA constructs per se, the holdings of that case is also applicable to claims such as those at issue here. Further, disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product. See Ariad, 598 F.3d at 1354-55 (“Regardless whether the asserted claims recite a compound, Ariad still must describe some way of performing the claimed methods... the specification must demonstrate that Ariad possessed the claimed methods by sufficiently disclosing molecules capable of reducing NF-kB activity so as to ‘satisfy the inventor’s obligation to disclose the technologic knowledge upon which the patent is based, and to demonstrate that the patentee was in possession of the invention that is claimed.’”) (internal citation omitted); see also Univ. of Rochester v. G.D. Searle& Co., Inc., 358 F.3d916,918 (Fed.Cir.2004) (applying the same analysis to assess written description for claims to a “method for selectively inhibiting” a particular enzyme by administering a functionally defined compound, i.e., a “non-steroidal compound that selectively inhibits activity” of the gene product for that enzyme).
In regards to claims to a product defined by function, without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 at1568 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”).
Further, in regards to a genus encompassing variants characterized by having an activity, structural features that distinguish the genus from others not encompassed by the genus are missing from the disclosure. No common structural attributes identify the members of the genus. The general knowledge and level of skill in the art do not supplement the omitted description because specific, not general, guidance is needed. In the instant case, there is not teaching as to which combinations of amino acids for each “X” would, or would not, result sin C3 or C3b binding. General knowledge in the art includes knowledge that some amino acid variations are tolerated without losing a protein’s structure; however, those of skill in the art would recognize that conservation of structure is not necessarily a surrogate for conservation of function. For example, Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) shows that a conservative replacement of a single “lysine” residue at position 118 of acidic fibroblast growth factor by “glutamic acid” led to a substantial loss of heparin binding, receptor binding and biological activity of the protein. Similarly, Lazar et al. ( Mol. Cell Biol. 8:1247-1252, 1988) teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 alone with alanine or asparagines 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 or what appears to be an inconsequential chemical modification will often dramatically affect the biological activity and characteristics of a protein.
The instant specification fails to provide sufficient descriptive information, such as definitive structural features that are common to the genus. That is, the specification provides neither a representative number of polypeptides that encompass the genus nor does it provide a description of structural features that are common to the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus. “[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the 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 to provide a "representative number” of species.
The functional requirements of the claimed polypeptides is the sort of wish list of properties which fails to satisfy the written description requirement because polypeptides encompassed by the claims with those properties have not been adequately described. Centocor, 636 F.3d at 1352. 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. EliLilly and Co.,598 F.3d 1336, 1353 (Fed. Cir. 2010).
Since the disclosure fails to describe common attributes or characteristics that adequately identify members of the genus, and because the genus is highly variant, the disclosure is insufficient to describe the genus. Thus, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus as broadly claimed.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “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). As discussed above, even though Applicant may propose methods of screening for possible members of the genus, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus, 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 isolation. The compound 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. See Ariad, 94 USPQ2d at 1161; Centocor at 1876 (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”)
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. The specification provided only the bovine sequence. 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 Interpretation
The claims recite proteins comprising a C3 and/or C3b binding polypeptide, wherein the amino acid sequence of the C3 and/or C3b binding polypeptide has various limitations – such as amino acids in various positions. Due to the “or” in independent claims (see: the “or” at line 2 of claim 1, the “or” at line 2 of claim 39, the “or” at line 1 of claim 74), claims encompass C3 binding proteins and C3b binding proteins that do not comprise amino acids at recited positions.
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.
Claim(s) 1, 26, 27, 31, 32, 38-41, 59, 63, 67, 72, 74, 82-84, 95, 96, 99, 100, and 118 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Her et al (WO 2013/082563 A1; 6/6/13).
Her et al teaches fusion proteins comprising a first binding domain that binds specifically to a component of the complement pathway (such as C3, C3b, C4b, iC3b, C3dg, CIq, or MBP) and a second domain with binding specificity to VEGF ([0063], [0052], and claims 1-3, in particular). Her et al further teaches the fusion proteins wherein the second domain is an antibody fragment such as a Fab ([0057], in particular). Her et al further teaches the fusion proteins further comprising a half-life extending polypeptide (claim 7, in particular), nucleic acids encoding the protein (claim 28, in particular), pharmaceutical compositions comprising the protein and a pharmaceutically acceptable carrier (claim 26). Her et al further teaches administering an effective amount of the fusion proteins to subjects with macular degeneration (claim 37, in particular) and that such administration can be to the eye of the subject ([0139], in particular).
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.
Claim(s) 1, 26, 27, 31, 32, 38-41, 59, 63, 67, 72, 74, 82-84, 87, 95, 96, 99, 100, and 118 is/are rejected under 35 U.S.C. 103 as being unpatentable over Her et al (WO 2013/082563 A1; 6/6/13) as applied to claims 1, 26, 27, 31, 32, 38-41, 59, 63, 67, 72, 74, 82-84, 95, 96, 99, 100, and 118 above, and further in view of Shandilya et al (US 2016/0289314 A1; 10/6/16).
Teachings of Her et al are discussed above.
Her et al does not specifically teach the second domain comprising the VEGF binding domain comprises an antigen binding domain heavy chain comprising SEQ ID NO:36 and a light chain comprising SEQ ID NO:35. However, these deficiencies are made up in the teachings of Shandilya et al.
Shandilya et al teaches the VEGF inhibitor ranibizumab, which is a Fab antibody fragment that binds VEGF ([0005] and [0072], in particular), comprises a heavy chain comprising SEQ ID NO:4 and light chain comprising SEQ ID NO:2 ([0017], in particular). SEQ ID NO:4 is identical to instant SEQ ID NO:36 and SEQ ID NO:2 is identical to instant SEQ ID N O:35.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of generating fusion proteins of Her et al (including a fusion protein that binds (i) C3 or C3b and (ii) VEGF) wherein the Fab of the fusion proteins that binds VEGF is ranibizumab of Shandilya et al because Shandilya et al teaches ranibizumab as a Fab antibody fragment that binds and inhibits VEGF ([0005] and [0072], in particular). This is an example of a simple substitution of one known element for another to obtain predictable results. This is also an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Conclusion
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/SEAN E AEDER/ Primary Examiner, Art Unit 1642
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