DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
The amendments and remarks filed 8/13/25 are acknowledged. Claims 1 and 8 have been amended. Claims 3-7, 11-47, 52-53, 55-65, and 67-74 have been canceled. Claims 1, 2, 8-10, 48-51, 54-55, 66, and 75 are pending.
Claims 50, 51, 54, 55, 66, and 75 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 1/13/25.
Claims 1,2, 8-10, and 48-49 are under examination as they read on the elected species.
Withdrawn Objections and Rejections
The objection to the drawings is withdrawn in light of the Applicant’s amendment thereto. See paragraph 5, page 2 of the previous Office action.
The rejection claim 8 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AlA), 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or a joint inventor (or for applications subject to pre-AlA 35 U.S.C. 112, the applicant), regards as the invention, is withdrawn in light of Applicant’s amendment thereto. See paragraph 8, page 10 of the previous Office action.
The rejection of claims 1, 2, 8, 9, 14, 15, 48, and 49 under pre-AlA 35 U.S.C. 102(e) as being anticipated by Soegaard et al. (US Patent Application Publication 2005/0226885 A1, published October 13, 2005), is withdrawn in light of Applicant’s amendment thereto. See paragraph 10, page 11 of the previous Office action.
The rejection of claims 1, 2, 8, 9, 10, 11, 14, 15, 17, 48, and 49 under pre-AlA 35 U.S.C. 102b as being anticipated by Gillies et al. (US Patent Application Publication 2008/0025947 A1, published January 31, 2008), is withdrawn in light of Applicant’s amendment thereto. See paragraph 11, page 12 of the previous Office action.
New Rejections Necessitated by Applicant’s Amendment
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 1,2, 8-10, and 48-49 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.
The claims are drawn to an immunoglobulin fusion protein comprising a first heavy chain, wherein the first heavy chain comprises an IgG heavy chain comprising a CH1, a heavy chain hinge, and a CH2, and a first light chain fusion protein, wherein the light chain fusion protein comprises:
an immunoglobulin light chain constant region and an IL2 fused to the C-terminus of the immunoglobulin light chain constant region, wherein the immunoglobulin fusion protein comprises a disulfide bond between a C-terminal Cys of the light chain and a Cys of the heavy chain hinge, and wherein the immunoglobulin fusion protein binds specifically to a tumor-associated antigen.
The specification discloses an antibody against GD2 (14.18 antibody) engineered to include IL-2 fused to the C-terminus of the light chain (See examples 1-13). The specification teaches that the immunocytokine produced is a whole antibody HL chain dimer containing two molecules of IL-2 per antibody (See page 37). The specification teaches fusion protein ch14.18-IL-2-L containing the fusion protein of SEQ ID NO: 1 (IL-2 fused to the light chain) (See page 40). The specification additionally discloses immunocytokines comprising GD2-IL-2 fusions having the amino acid sequences set forth in SEQ ID NOs. 1-6 and 10 (See page 50).
The immunoglobulin fusion proteins having the amino acid sequences set forth in SEQ ID NOs: 1-6 and 10 meet the written description provision of the 35 U.S.C. 112 first paragraph. However, the claims encompass far more than the aforementioned fusion proteins. The claims encompass a genus of fusion proteins comprising any IgG immunoglobulin and IL2 that have no correlation between their structure and function.
Regarding the term "immunoglobulin", the claims are overly broad due to the number of proteins encompassed by the term “immunoglobulin”. The immunoglobulin portion of the fusion is not limited to any particular agent, and thus, the term encompasses immunoglobulins that bind any tumor antigen (See pages 22 and 23 of the specification). In other words, the claims encompass all known and unknown immunoglobulins that bind to any tumor-associated antigen. However, with the exception of the anti-human GD2 antibody, designated 14.18, the specification does not provide guidance regarding the structure of the immunoglobulin that is encompassed by the claims.
Regarding the IL2, the claims encompass a genus of IL2 proteins that are not limited to the full-length IL2, but rather, broadly encompass variants and fragments having various truncations and amin acid substitutions. However, with the exception of the specific IL2 proteins having specific sequences, the specification does not provide guidance regarding the structure of the IL2 that is encompassed by the claims.
Additionally, the specification does not provide a representative number of species commensurate with the scope of the genus. With the exception of the fusion proteins having the amino acid sequences set forth in SEQ ID NOs: 1-6 and 10, the specification has not disclosed sufficient species that are representative of the genus. It should be noted that the aforementioned fusion proteins having the amino acid sequence set forth in SEQ ID NOs: 1-6 and 10 comprise a single immunoglobulin (chimeric 14.18) and full-length IL-2. However, the claims encompass far more than these species. The fusion protein can encompass any immunoglobulin that binds to any tumor associated antigen. Thus, the chimeric 14.18 immunoglobulin fused to IL-2 is not deemed to be representative of all immunoglobulins encompassed by the claims. 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.)
With the exception of the fusion proteins having the amino acid sequence set forth in SEQ ID NOs: 1-6 and 10, 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. The specification provided only the bovine sequence.
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 USPQ2d 1966.
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. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]. "See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) "[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when ... the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).
Protein chemistry is probably one of the most unpredictable areas of biotechnology. Consequently, the effects of sequence dissimilarities upon protein structure and function cannot be predicted. Bowie et al. (Science, 1990, 247:1306-1310) teach that an amino acid sequence encodes a message that determines the shape and function of a protein and that it is the ability of these proteins to fold into unique three-dimensional structures that allows them to function and carry out the instructions of the genome and further teaches that the problem of predicting protein structure from sequence data and in turn utilizing predicted structural determinations to ascertain functional aspects of the protein is extremely complex (column 1, page 1306). Bowie et al. further teach that while it is known that many amino acid substitutions are possible in any given protein, the position within the protein's sequence where such amino acid substitutions can be made with a reasonable expectation of maintaining function are limited. Certain positions in the sequence are critical to the three dimensional structure/function relationship and these regions can tolerate only conservative substitutions or no substitutions at all (column 2, page 1306). 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) 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. Additionally, Bork (Genome Research, 2000; 10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2). Given not only the teachings of Bowie et al., Lazar et al. and Burgess et al. but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed proteins could not be predicted based on sequence identity to insulin. Clearly, it could not be predicted that polypeptide or a variant that shares only partial homology with a disclosed protein or that is a fragment of a given protein will function in a given manner (i.e. inducing migration while not inducing cytokine and chemokine production).
The state of the art regarding IL-2 muteins with reduced activity is discussed by Shanafelt et al. (US Patent 6,955,807 B1, issued October 18, 2005). Shanafelt et al. teach that appropriate substitution at Asp-20, Asn-88 or Gln-126 reduced the binding interactions for either IL-2Rβ (Asp-20 and Asn-88) or IL-2Rγ (Gln-126) (See column 8). Shanafelt et al. teach that the net effect of such substitutions resulted in IL-2 muteins that retained activity on human T cells, and have reduced activity on human NK cells (See column 8). Shanafelt et al. disclose single amino acid mutations resulting in reduced affinity for the intermediate IL-2 receptor (See table 1). However, it should be noted that Shanafelt et al. state that it is not possible to predict the outcome of a given substitution prior to evaluation of each IL-2 mutein in T and NK cell assays (See columns 8 and 9). Thus, the reference provides evidence that one cannot readily predict that a particular amino acid mutation in IL-2 will result in the function of having reduced binding affinity for the intermediate IL-2 receptor. Furthermore, as noted by Bowie et al., even conservative substitutions can affect the structure/function relationship of a protein.
Accordingly, one of skill in the art would conclude that the claimed invention encompasses a plurality of fusion proteins that may not have the biological function that is recited in the present claims. It should be noted that the claimed invention encompasses the fusion proteins having the amino acid sequence set forth in SEQ ID NOs: 1-6 and 10, as well as a plurality of fusion proteins comprising any immunoglobulin fused to IL2. With the exception of the fusion proteins having the amino acid sequence set forth in SEQ ID NOs: 1-6 and 10, the instant specification does not describe any fusion proteins that are capable of having the claimed functions. Based on the teachings of the instant specification and the prior art one of skill in the art would not conclude that Applicant was in possession of the claimed genus of fusion proteins.
Therefore, only the fusion proteins having the amino acid sequence set forth in SEQ ID NOs: 1-6 and 10, but not the full breadth of the claims (fusion proteins comprising all IgG immunoglobulins) meet the written description provision of 35 USC 112, first paragraph. The species specifically disclosed is not representative of the genus because the genus is highly variant. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 USC 112 is severable from its enablement provision. (See page 1115).
Applicant’s Arguments
Applicant argues that the claims have been amended to encompass fusion proteins comprising an IgG heavy chain comprising a CH1, a heavy chain hinge, and a CH2, and a light chain fusion protein comprising an IL2 fused to the C-terminal cysteine of the light chain fusion protein. Applicant argues that the claims encompass a subset of specified IgG heavy chain comprising a CH1, a heavy chain hinge, and a CH2. Applicant argues that furthermore, the claims are limited to IL2 that are fused to the C-terminal cysteine of an antibody light chain. Applicant argues that IgG and IL2 are well known in the art, and the specification describes a representative number of species of IL2.
Response to Arguments
Applicant’s arguments have been fully considered but they are not persuasive.
Although the claims have been amended to recite that the immunoglobulin comprises a first heavy chain, wherein the first heavy chain comprises an IgG heavy chain comprising a CH1, a heavy chain hinge, and a CH2, and a first light chain fusion protein, wherein the light chain fusion protein comprises an immunoglobulin light chain constant region and an IL2 fused to the C-terminus of the immunoglobulin light chain constant region, the claims are still of inclusive of a vast genus of immunoglobulin fusion proteins that are not adequately described by the specification. As stated in MPEP 2168, for inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is require to show possession. Here, the claims recite immunoglobulin fusion proteins comprising a first heavy chain, wherein the first heavy chain comprises an Ig G heavy chain comprising a CH1, a heavy chain hinge, and a CH2, and a first light chain fusion protein, wherein the light chain fusion protein comprises: an immunoglobulin light chain constant region and an IL2 fused to the C-terminus of the immunoglobulin fusion protein that has the required function of binding to a tumor antigen. The claim recites a generic IgG for the structure of the immunoglobulin. As presented above, the field of protein biochemistry is unpredictable and it cannot be predicted whether an immunoglobulin will have the function of binding to a particular tumor antigen.
Applicant relies on the disclosure of the chimeric antibody 14.18, which binds to the tumor antigen GD2, fused to the full-length IL2; however, the genus is far broader than the species disclosed. Although the term “immunoglobulin” does impart some structure, the structure that is common to immunoglobulins is generally unrelated to its specific binding function; therefore, correlation is less likely for immunoglobulins than for other molecules. Accordingly, the specification does not any structural features commonly possessed by members of the genus, because, while the description of an ability of the claimed immunoglobulin may generically describe that molecule’s function, it does not describe the molecule itself. A definition by function does not suffice to define the genus because it is only an indication of what the antibody does, rather than what it is; therefore it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the genus of immunoglobulins is highly variable (i.e. each different immunoglobulin capable of binding to any given tumor antigen would necessarily have a unique sequence of amino acids; see MPEP 2434), the functional characteristic of binding to something specific, is insufficient to describe the genus. Further, given the highly diverse nature of immunoglobulins, particularly in CDRs, even one of skill in the art cannot envision the structure of an immunoglobulin by only knowing its binding characteristics. Further, as noted above, IL2 is not limited to the full length IL2, and the term encompasses fragments and variants comprising any number of truncations and amino acid substitutions. Thus, the specification does not provide substantive evidence for possession of this large and variable genus, encompassing a potentially massive number of immunoglobulins fused to IL2 fragments and variants claimed only by a functional characteristic(s) and/or partial structure.
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.
Claim 8 is 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.
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 8 recites the broad recitation IL2, and the claim also recites human IL2, human IL2 that is shortened by 1-10 or 1-5 N-terminal amino acids of SEQ ID NO: 13, an IL2 wherein 10-25 amino acids are located between the C-terminal of Cys of the light chain constant region and a position in the cytokine corresponding to D20 of human IL2 of SEQ ID NO: 13, an IL2 comprising a mutation at one or more positions corresponding to D20, F42, R38, N88, or Q126 in human IL2 of SEQ ID NO: 13, and an IL2 comprising a Q126W mutation corresponding to human IL2 of SEQ ID NO: 13, each of which is the narrower statement of the range/limitation. The claim(s) 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 10 recites the limitation "the non-immunoglobulin fusion peptide". There is insufficient antecedent basis for this limitation in the claim. Base claim 1 recites that the immunoglobulin light chain is fused to IL2 and does not reference a non-immunoglobulin fusion peptide. The specification establishes that the non-immunoglobulin fusion peptide encompasses IL2; however, because the term non-immunoglobulin fusion peptide is broader in scope than IL2, it is unclear is how applicant intends to further limit claim 1 by the recitation of the “non-immunoglobulin fusion peptide”. Clarification and/or correction is required.
Amending claim 10 to recite “wherein the immunoglobulin light chain constant region and the IL2 are fused via a linker” would obviate the rejection.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 10 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Although claim 10 depends from a preceding claim, claim 10 does not further limit the claims from which it depends. Claim 1 states that an IL2 is fused to the C-terminus of the immunoglobulin light chain region. However, claim 10 refers to a “non-immunoglobulin fusion peptide” as the fusion partner of the immunoglobulin light chain constant region. Although the specification establishes that the non-immunoglobulin fusion peptide encompasses IL2, it is clear that the term also encompasses other protein beyond IL2. Thus, claim 10 is broader in scope that the claim from which it depends, and does not further limit claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Status
No claims are allowed.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/SANDRA CARTER/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674