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 .
The amendments and remarks filed 12/2/25 are acknowledged. Claims 2, 5-13, and 18-22 have been canceled. Claims 1, 3-4, and 14-17 are pending and under examination.
Maintained Rejection
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, 3-4, and 14-17 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 method of treating a patient suffering from a non-small cell lung cancer (NSCLC) driven by deregulated Human Epidermal Growth Factor Receptor (HER/Human EGFR), wherein the patient has a tumor expressing a mutated form of the EGFR and increased levels of STAT3 activation, comprising: administering to a patient in need of such treatment a regimen which combines administration of a tyrosine kinase inhibitor (TKI) selected from the group consisting of gefitinib, erlotinib, afatinib, dacomitinib, and pharmaceutically acceptable salts thereof, with administration of a recombinant protein having 95%, 96%, 97%, 98%, 99%, or 100% amino acid identity to SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 20, wherein any substitutions are conservative of the sequence’s original function, wherein the TKI is administered according to a continuous regimen based on an average daily dose in the range of 10 to 150 mg and the recombinant protein is co-administered according to a therapeutically effective amount to reduce STAT3 activation repeated thrice, twice or once a week, once in two weeks, once in three weeks or at least once monthly.
The specification teaches that anti-EGF antibodies (“Ab2” or “Bioven anti-EGF2 antibodies) were derived from immunization of rabbits with a recombinant fusion molecule containing modified CTB and EGF sequences. The specification teaches that the immunogenic recombinant fusion molecule is shown in SEQ ID NO: 1 and further described FIG. 20A. The specification teaches that additional anti-EGF antibodies can be derived from immunization of rabbits with a recombinant fusion molecule containing CTB and EGF sequence and is shown in SEQ ID NO: 2 and further described in FIG. 20B.
The issue with regard to the written description provision is that the genus of recombinant proteins that are not adequately described. Although the claims are inclusive of the recombinant proteins having the amino acid sequence set forth in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 20, the claims also broadly encompass recombinant proteins that are fragments having 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:1, SEQ ID NO: 2, or SEQ ID NO: 20 to generate active immunization targeting EGF. A variance of 95%, for example, in the polypeptide set forth in SEQ ID NO: 1 that is 234 amino acids in length translates into 11 residues that may be added, deleted, substituted, or otherwise mutated anywhere throughout the entire length of the 234-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%. Applicants have not described which domain or portions of SEQ ID NOs: 1-6 that 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).
Furthermore, Applicants have not shown possession of a representative number of species that have the claimed function(s). While the specification clearly sets forth a correlation between the recombinant proteins having the amino acid sequences set forth in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 20, and the function of having EGF activity, 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 recombinant EGF proteins, and encompass variants and fragment of the full-length recombinant proteins. 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. Therefore, given the lack of structure function correlation and the lack of a representative number of species, 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 recombinant polypeptides set forth in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 20 in combination with a TKI selected from the group consisting of gefitinib, erlotinib, AZD9291, and afatinib, the skilled artisan cannot envision the detailed chemical structure of the encompassed combination therapies, 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.
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). Moreover, Defeo-Jones et al. (Molecular and Cellular Biology, Sept. 1989, p. 4083-4086) teach that the conservative substitution of lysine for arginine at position 42 completely eliminated biological activity (See abstract and pages 4084-4085). 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., Burgess et al., and Defeo-Jones 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 based on sequence identity. 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 SEQ ID NO. will function in a given manner. Therefore, the state of the art supports that even the skilled artisan requires guidance on the critical structures of the agent per se and thereby does not provide adequate written description support for which structural features of any given polypeptide would predictably retain their functional activities.
Applicant is reminded that generally, in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus (Enzo Biochem, Inc. v. Gen- Probe Inc., 323 F.3d 956 (Fed. Cir. 2002); Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004); Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997)). A patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017) at page 1358). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
Adequate written description requires more than a mere statement that is part of the invention. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chungai 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.
The 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 USPQ2dat1966.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, ‘does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the “written description" requirement is broader than to merely explain how to "make and use"; the 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 Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and 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. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed. Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Applicant’s Arguments
Applicant argues that the claims limited to proteins having a particular function. Applicant argues the claims are limited to recombinant proteins having 95-100% amino acid identity to SEQ ID NOs: 1, 2, or 20 used in combination with a tyrosine kinase inhibitor to treat non-small cell lung carcinoma driven by deregulation EGFR, in patients whose tumors contain an EGFR mutation and increased STAT3 activation. Applicant argues that the genus is extremely narrow and functionally defined class of proteins. Further, the claims specify that any substitutions are conservative with respect to the defined function. Accordingly, the scope does not encompass "millions" of proteins as asserted, but rather a constrained set of variants with a high degree of similarity to the disclosed sequences. Applicant argues that the specification provides multiple disclosed sequences (SEQ ID NOs: 1, 2, and 20), each distinct in structure yet each demonstrating the claimed function. None of these are "widely variant" in the sense contemplated by Enzo. Instead, they serve as representative species that reflect the inventors' possession of a structurally related, functionally constrained genus.
Applicant argues that conservative substitutions and high sequence identity (over 95%) can predictably maintain function. Applicant's specification does not claim a laundry list of sequences and substitutions but instead focuses on a limited class of proteins and variants that perform the claimed function of treating non-small cell lung cancer (NSCLC) driven by deregulated EGFR, in patients whose tumors contain an EGFR mutation and increased STAT3 activation. One having skill in the art would clearly recognize that the claimed protein is not an unpredictable collection of proteins but, a narrow a functionally constrained group of variants.
Response to Arguments
Applicant’s arguments have been fully considered but they are not persuasive. The
specification does not adequately describe the variants having 95-99% amino acid identity to SEQ ID NOs: 1, 2, and 20 recited in the claims. To give an idea of the breadth of the claims, the EGFR polypeptide set forth in SEQ ID NO: 1 has 234 amino acids. To reach at least 95% identity, up to11 amino acids can be varied at any position within the sequence. Mutating 11 sites out of 234 results in 1.15x1026 possible mutation site combination. Substitutions at the site can be selected from 19 other potential amino acids. Selecting 11 sites with 19 difference amino acids gives over 1.16x1014 possible combination, and that is just for one set of substitutions out of all possible combinations. Therefore, contrary to Applicant’s arguments, there are in fact millions of possible recombinant polypeptides encompassed by the claims.
MPEP 2163 states that "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 i)(C), above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406." (emphasis added by the Examiner). In the instant case, the functional characteristics are given without describing the correlation with a particular structure for the peptide. The description of SEQ ID NO:1,2, and 20 is supported.
It is the requirement for specific functions (i.e. "treating a patient suffering from a NSCLC driven by deregulated HER/Human EGFR” and “reduce STAT3 activation”) that are not present within the entire encompassed genus of recombinant proteins that necessitates the rejection. In other words, considering the wide range of proteins that are present that vary in sequence, one of skill in the art would not be able to "immediately envisage" the claimed proteins that possess the required functions. One of skill in the art would have to screen for the peptides that could perform the required functions. The specification provides no guidance regarding the structures that must be present for the proteins to be capable of these required functions. Thus, the proteins described by the instant specification have no correlation between their structure and their function, and the specification does not set forth a representative number of species for such a broad genus of proteins.
Regarding Applicant’s argument that conservative substitutions are known in the art, it is well known that even a single amino acid change can alter the function of a protein, and thus, changing any given amino acid is unpredictable. Even if a conservative substation was made, it cannot be predicted that the protein would maintain its function. As taught by Defeo-Jones et al., even conservative substitutions can alter a proteins function. Therefore, with no guidance form the specification, those of skill in the art are unable to identify the genus of millions of encompassed polypeptides that have the functions required by the claims without engaging in screening assays. Therefore, one of skill in the art is left to guess what changes can be made. More importantly, if one cannot predictably determine the variants of SEQ ID NOs: 1, 2, and 20, then Applicant did not supply sufficient information about the invention, and clearly did not possess the full genus encompassed by the claims. Therefore, the specification provides insufficient written description to support the genus encompassed by the claims.
Claim Status
No claims are allowed.
Conclusion
THIS ACTION IS MADE FINAL. 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