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 .
Applicant’s election without traverse of group I, claims 1, 4, 7-10, 12, 15, 18-20, 22, 25, 26, and 33, and the species of the anti-AREG antibody defined by the sequences of SEQ ID NOs: 67, 83, 1, 15, 16, 47, 44, and 46, and the ectodomain of TRII having SEQ ID NO: 90 in the reply filed on 9/2/26 is acknowledged.
Claims 29-31 and 35-36 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 9/2/26.
Claims 1, 4, 7-10, 12, 15, 18-20, 22, 25, 26, and 33 are under examination as they read on the elected species.
Drawings
The description of the drawings is objected to. According to 37 CFR 1.74, when there are drawings, there shall be a brief description of the several views of the drawings and the detailed description of the invention shall refer to the different views by specifying the numbers of the figures, and to the different parts by use of reference letters or numerals (preferably the latter). The examiner should see to it that the figures are correctly described in the brief description of the drawing, that all section lines used are referred to, and that all needed section lines are used. If the drawings show Figures 1A, 1 B, and 1C and the brief description of the drawings refers only to Figure 1, the examiner should object to the brief description, and require applicant to provide a brief description of Figures 1A, 1 B, and 1C. In the instant case, Figure 7 has parts A, B, and C that are not individually described. Figure 14 has parts A, B, and C that are not individually described. Figure 15 has parts A, B, and C that are not individually described. See MPEP 608.01(f)
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, 4, 7-10, 12, 15, 18-20, 22, 25, 26, and 33 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 MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
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, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, 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 Applicants were in possession of the claimed genus.
The instant claims are drawn to a bi-functional fusion protein comprising a first domain and a second domain, wherein the first domain is capable of binding to AREG or a fragment thereof, preferably is an antibody or an antigen-binding fragment thereof that binds to AREG or a fragment thereof, and the second domain is capable of binding to a TGFβ ligand or a fragment thereof, preferably comprises a part of the ectodomain of TGFβ receptor II (TRII) or a variant thereof.
The specification discloses anti-AREG/TRII, which is an anti-AREG antibody-ectodomain of TGFβRII (TRII) bifunctional protein. The light chain variable region of the molecule is identical to that of the anti-AREG antibody (SEQ ID No:70-89). The heavy chain of the molecule is a fusion protein comprising the heavy chain of the anti-AREG antibody (SEQ ID No.:57-69) genetically fused to the N-terminus of the soluble TRII (SEQ ID No.:90-107) via a flexible linker (SEQ ID No.:108, 109, 113, and 116-117). At the fusion junction, the C-terminal 15 lysine residue of the antibody heavy chain was mutated to alanine to reduce proteolytic cleavage.
Regarding the first domain capable of binding to AREG or a fragment thereof portion of the fusion protein, although the claims are inclusive of the anti-AREG antibodies comprising specifically defined VH region, VL region, HCDR1-3 and LCDR13 sequences, the claims also include (i) functionally defined antibodies, (ii) antibody and antigen-binding fragments thereof comprising amino acid sequences that have 1-5 amino acid substitutions, and (iii) antibodies comprising VH and VL sequences having at least 95% sequence identity to the claimed VH and VL sequences. This would represent a large pool of variant antibodies that must have similar functional activity. For example, a variance of 95%, for example, in the VH region set forth in SEQ ID NO: 67 that is 125 amino acids in length translates into 6 residues that may be added, deleted, substituted, or otherwise mutated anywhere throughout the entire length of the 125 residue amino acid polypeptide. There is no limit in the claims, as written, that the variance be contiguous. Moreover, there is no limitation stating that the substitution, for example, be a conservative substitution. As a result, there are potentially thousands of variant permutations that could be made and still maintain a variance of 95%. It should be noated that this example is for only one VH region sequence, and consideration of the other portions of the fusion protein would exponentially increase the breadth of the claims. Thus, the claims encompass a vast genus of antibodies and variants that must have similar functional activity. However, the specification does not describe which domains or portions of the recited sequences are critical to the function of the antibody. Although the term “antibody” does impart some structure, the structure that is common to antibodies is generally unrelated to its specific binding function, therefore, correlation is less likely for antibodies than for other molecules. Further, given the highly diverse nature of antibodies, particularly in CDRs, even one of skill in the art cannot envision the structure of an antibody by only knowing its binding characteristics. Thus, these structures (i.e., sequence variants) are claimed only by their functional characteristics and the specification fails to provide sufficient correlation between the claimed functional characteristics (i.e., specifically bind AREG) and the necessary structural components (i.e., critical domains within the sequences).
Regarding the second domain capable of binding to a TGFβ ligand or a fragment thereof portion of the fusion protein, while the claims are inclusive of the TRII having the sequence set forth in SEQ ID NO: 90, the claims also include any amino acid sequence that has at least 85% identity to SEQ ID NO:90 and that also has the function of binding TGFβ ligand. This would represent a large pool of variant polypeptides that must have similar functional activity. A variance of 15%, for example, in the polypeptide set forth in SEQ ID NO: 90 that is 136 amino acids in length translates into 20 residues that may be added, deleted, substituted, or otherwise mutated anywhere throughout the entire length of the 136 residue amino acid polypeptide. There is no limit in the claims, as written, that the variance be contiguous. Moreover, there is no limitation stating that the substitution, for example, be a conservative substitution. As a result, there are potentially thousands of variant permutations that could be made and still maintain a variance of 85%. Applicants have not described which domain or portions of SEQ ID NO: 90 are critical to the function of the protein. The specification provides limited guidance regarding which amino acids can be modified in the genus of polypeptides, while maintaining any given function. Therefore, these structures (i.e. sequence variants) are claimed only be their functional characteristics and the specification fails to provide sufficient correlation between the claimed functional characteristics and the necessary structural components (i.e. critical domains within the sequences).
Thus, the genus of fusion proteins is extremely broad because the claims recite generic and incompletely described fusion proteins. One of ordinary skill in the art would not be reasonably apprised of the structure of the claimed fusion proteins without adequate descriptions of its component parts or overall makeup. The generically claimed AREG antibody, antigen-binding fragment or variant, and TGFβ ligand do not impart enough structural information to permit one of ordinary skill in the art to reasonably recognize or understand that Applicant was in possession of the full scope of the genus of fusion proteins recited in the claims. For instance, without knowing the structure of the claimed anti-AREG antibody and TGFβ ligand, one would not be able to adequately describe the claimed fusion protein. Therefore, the specification does not provide adequate written description to identify the broad and variable genus of fusion proteins because, inter alia, the specification does not disclose a correlation between the necessary structure of the fusion protein and the function(s) recited in the claims; and thus, the specification does not distinguish the claimed genus from others, except by function. Accordingly, the specification does not define any structural features commonly possessed by members of the genus, because while the description of an ability of the claimed fusion protein may generically describe the proteins’ function, it does not describe the fusion protein itself. A definition by function does not suffice to define the genus because it is only an indication of what the fusion protein 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 fusion proteins is highly variable (i.e., each fusion protein would necessarily have a unique structure; see MPEP 2434), the functional characteristic of being capable of binding to AREG or a fragment thereof, and capable of binding to a TGFβ ligand or fragment thereof is insufficient to describe the genus.
Further, applicants have not shown possession of a representative number of species of fusion proteins. As noted above, the claims are generic for the components of the fusion protein. Although the specification sets forth a correlation between the fusion proteins comprising although the claims are inclusive of the anti-AREG antibodies comprising specifically defined VH region, VL region, HCDR1-3 and LCDR13 sequences, and a TGFβ ligand comprising SEQ ID NO: 90, and the claimed functions, this correlation does not appear to be clearly present in the breadth of the claims. As noted above, the claims are not limited to the disclosed fusion proteins, and broadly encompass fusion proteins comprising sequence variants. Thus, the genus has substantial variation because of the numerous alternatives and combinations permitted. There is no description of the structure common to the members of the genus such that one of skill in the art can visualize or recognize the members of the genus. Therefore, only a few species have been described and this is not considered to be representative of the breadth of the genus.
MPEP §2163 states that for a generic claim, the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. If the genus has a substantial variance (as in the instant case), the disclosure must describe a sufficient variety of species to reflect the variation within that genus. Although the MPEP does not define what constitutes a sufficient number of representative species, the courts have indicated what does not constitute a representative number to adequately describe a broad genus. The courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus (e.g., see In re Gostelli, 872, F. 2d at 1012, 10 USPQ2d at 1618).
Further, the disclosure of only one or two 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 genu[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.") (MPEP 2163). “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). 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.)
Regarding the encompassed antibody and antibody fragments, the claims require various functional characteristics of the claimed antibodies and antibody fragments, including the ability to bind AREG or a TGFβ ligand. The functional characteristics of antibodies (including binding specificity and affinity are dictated on their structure. Amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. For example, Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28 at 416) teaches that, “ … Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site." The art shows an unpredictable effect when making single versus multiple changes to any given CDR. For example, Brown et al. (J Immunol. 1996 May; 156(9):3285-91 at 3290 and Tables 1 and 2), describes how the VH CDR2 of a particular antibody was generally tolerant of single amino acid changes, however the antibody lost binding upon introduction of two amino changes in the same region.
The claims encompass an extremely large number of antibodies that have specific required functions. Recently, the U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen V. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself even when preparation of such an antibody would be routine and conventional. Amgen, 872 F.3d at 1378-79. A key role played by the written description requirement is to prevent "attempt[s] to preempt the future before it has arrived." Ariad at 1353, (quoting Fiers V. Revel, 984 F.2d at 1171). Upholding a patent drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of antibodies. In the instant case, neither the art nor the specification provide a sufficient representative number of antibodies or a sufficient structure-function correlation to meet the written description requirements. Therefore, neither the art nor the specification provide a sufficient representative number of antibodies or a sufficient structure-function correlation to meet the written description requirements.
Regarding the encompassed proteins, 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. Punta et al. (PLoS Comput Biol 4(10): e1000160, 2008) teach that homology (both orthology and paralogy) does not guarantee conservation of function (See page 2). Punta et al. teach that relatively small difference in sequence can sometimes cause quite radical changes in functional properties, such as a change of enzymatic action, or even loss or acquisition of enzymatic activity itself (See page 2). Punta et al. teach that it is also apparent that there is no sequence similarity threshold that guarantees that two proteins share the same function (see page 2). Punta et al. teach that homology between two proteins does not guarantee that they have the same function, not even when sequence similarity is very high (including 100% sequence identity) (See page 2 and table 2). Punta et al. teach that proteins live and function in 3D, and therefore structural information is very helpful for predicating function (See page 4). However, as with sequence, two proteins having the same overall architecture, and even conserved functional residues, can have unrelated functions (See page 4). Punta et al. teach that still; structural knowledge is an extremely powerful tool for computational function prediction (See page 5).
Similarly, Whisstock et al. (Quarterly Reviews in Biophysics. 36(3):307-340, 2007) teach that the prediction of protein function from sequence and structure is a difficult problem (See abstract). Although many families of proteins contain homologues with the same function, homologous proteins often have different functions as the sequences progressively diverge (See page 309). Whisstock et al. teach that moreover, even closely related proteins can change function, either through divergence to a related function or by recruitment for a very different function (See page 309). Further, Whisstock et al. note that in some instances, even sequences that are the same can have different functions. For example, eye lens proteins in the suck are identical in sequence to active lactate dehydrogenase and enolase in other tissues, although they do not encounter the substrates in the eye (See page 310). Whisstock et al. teach that assigning a function to an amino acid sequence based upon similarity becomes significantly more complex as the similarity between the sequence and a putative homologue fall (See page 321). Whisstock et al. teach that while it is hopeful that similar proteins will share similar functions, substitution of a single, critically placed amino acid in an active-site may be sufficient to alter a protein’s role fundamentally (See pages 321-323).
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 Song et al. (Molecular Biology of the Cell, 15:1287–1296, March 2004) who teach that substitution of alanine for aspartate in survivin results in the conversion of survivins’ apoptotic function from anti-apoptotic to proapoptotic and changes in its subcellular localization (See page 1287-1289). 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 Punta et al., Whisstock et al., Song 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 having the required function(s) could not be predicted.
Applicant has provided little or no descriptive support beyond the mere presentation of generic or partially named structures to enable one of ordinary skill in the art to determine the actual structural composition of the claimed genus of fusion proteins. Although the prior art outlines art-recognized procedures for producing and screening for recombinant proteins this is not sufficient to impart possession of the genera of variant proteins to Applicant. Even if a few structurally identifiable composition components were described in the specification, they may not be sufficient, as the ordinary artisan would not necessarily immediately recognize how to put them together in such a way as to form a completely constructed fusion protein such that one would be able to distinguish it from the fusion proteins of the prior art. Without an adequate structural description of the claimed components and descriptive support on how to put them together, one of ordinary skill in the art would not be reasonably apprised that Applicant was in possession of the genus of recombinant proteins as claimed.
While "examples explicitly covering the full scope of the claim language" typically will not be required, a sufficient number of representative species must be included to "demonstrate that the patentee possessed the full scope of the [claimed] invention." Lizard tech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724,1732 (Fed. Cir. 2005).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the claimed method which encompasses treating any cancer. 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, Univ. of Rochester v. G.D. Searle& Co., 358 F.3d 916,927, 69 USPQ2d 1886, 1895 (Fed. Cir. 2004); accord Ex Parte Kubin, 2007-0819, BPAI 31 May 2007, opinion at p. 16, paragraph 1). 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).
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).
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 1, 4, 7-10, 12, 15, 18-20, 22, 25, 26, and 33 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.
Claims 1, 4, 12, 15, 18, 22, and 25 recite the term “preferably” which renders the claim indefinite because one cannot ascertain the metes and bounds of what is and is not included. See MPEP § 2173.05(d). Claims 7-10, 19-20, 26, and 33 do not cure the deficiency of claim 1, and thus, are included in the rejection.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 4, 12, 20, and 33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Johnston et al. ((US Patent Application Publication 2010/0111965 A1, published May 6, 2010) in view of Gu et al. (US Patent Application Publication 2020/0157180 A1, published May 21, 2020).
The instant claims are drawn to a bi-functional fusion protein comprising a first domain and a second domain, wherein the first domain is capable of binding to AREG or a fragment thereof, preferably is an antibody or an antigen-binding fragment thereof that binds to AREG or a fragment thereof, and the second domain is capable of binding to a TGFβ ligand or a fragment thereof, preferably comprises a part of the ectodomain of TGFβ receptor II (TRII) or a variant thereof.
Johnston et al. teach a pharmaceutical composition comprising two EGF inhibitors for treating neoplastic disorders (See claim 1 and paragraph 0012-0013). Johnston et al. teach that the first EGF is HB-EGF and said second EGF is selected from the group consisting of AREG, TGF, EREG, BTC, and NRG3 (See claim 41). Johnston et al. teach that the inhibitor of EGF may target AREG and the EGF inhibitor is an anti-AREG antibody (See paragraph 0028 and claim 43). Johnston et al. teach that the EGF inhibitors can be used simultaneously (See paragraph 0013). Johnston et al. teach that the EGF inhibitor for use in the invention may be in the form of an immunoconjugate, comprising an antibody fragment conjugated to an "active therapeutic agent" (See paragraph 0120).
Johnston et al. do not teach wherein the anti-AREG antibody is fused to a second domain that is capable of binding to a second TGFß ligand.
Gu et al. teach a fusion protein containing a targeting moiety and a TGF-β receptor moiety, wherein the TGF-β receptor moiety is an N-terminal truncated form of the extracellular domain of TGF-βRII (See paragraph 0009). Gu et al. teach that the extracellular domain of TGF-βRII has the amino acid sequence of SEQ ID NO: 13; which is 100% identical to the amino acid sequence of SEQ ID NO: 90 of the instant claims. Gu et al. teach that the targeting moiety is a cell- specific targeting moiety; preferably, the targeting moiety is a cancer cell-specific targeting moiety (See paragraph 0012). Gu et al. teach in a preferred embodiment of the present invention, the cancer cell-specific targeting moiety is selected from the group consisting of an antibody or antigen-binding fragment thereof, a growth factor, a hormone, a peptide, a receptor and a cytokine (See paragraph 0013).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to form a fusion protein comprising the anti-AREG antibody of Johnston et al. and the extracellular domain of TGF-BRII of Gu et al. because the Supreme Court set forth in KSR International Co. V. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the prior art contained a product which differed from the claimed product by the substitution of some component with another component, where both components are known in the art, and one of ordinary skill in the art could have substituted one known element for another to yield predictable results, the substitution of one known element for another would have been obvious. In the instant case, Johnston et al. teach a composition comprising two separate EGF inhibitors, and teach the first EGF inhibitor is HB-EGF and the second EGF inhibitor is an anti-AREG antibody. Johnston et al. teach that the EGF inhibitors can be in the form of an immunoconjugate. Johnston et al. further teach that any molecule that inhibits EGF can be used in the immunoconjugate. Gu et al. teach a fusion protein comprising a targeting moiety and the extracellular domain of TGF-BRII. It would be obvious that the immunoconjugate of Johnston et al. could be modified to substitute the extracellular domain of TGF-BRII, as taught by Gu et al., for the HB-EGF, since Johnston et al. teach that any molecule which reduces expression of an EGF gene or antagonizes the EGF protein may be used as the EGF inhibitor in the immunoconjugate comprising two different EGF inhibitors. The substitution of the extracellular domain of TGF-βRII for the HB-EGF would require no alterations in the immunoconjugate and the immunoconjugate would still function in the same manner, which is to provide two different EGF inhibitors to dramatically reduce tumor cell growth and proliferation. One of ordinary skill in the art would have a reasonable expectation of success because each of the inhibitors has been shown to inhibit EGF and the art teaches that the EGF inhibitors can be constructed as fusion proteins for simultaneous use. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
TGFβRII Sequence Alignment
ALIGNMENT:
Query Match 100.0%; Score 759; Length 136;
Best Local Similarity 100.0%;
Matches 136; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 IPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEV 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 IPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEV 60
Qy 61 CVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDEC 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 CVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDEC 120
Qy 121 NDNIIFSEEYNTSNPD 136
||||||||||||||||
Db 121 NDNIIFSEEYNTSNPD 136
Claim Status
No claims are allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SANDRA CARTER whose telephone number is (571)272-2932. The examiner can normally be reached 8:00-5:00 pm.
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/SANDRA CARTER/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674
