DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Newly submitted claims 43-45 are directed to an invention that is independent or distinct from the invention originally claimed for the following reasons: the original claims presented a synthetic ligand polypeptide comprising at least two binding domains that bind to an extracellular domain of a cytokine receptor polypeptide subunit where the binding domains are monovalent antibodies. The newly added claims are directed to a completely different type of protein molecule, comprising comprise cytokine domains, not antibodies. The invention that has been examined is directed to the antibodies of the originally presented claims.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claims 43-45 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Claim Status
The amendments and arguments filed 10/16/25 are acknowledged. Claims 1-23, 26, and 32-42 are cancelled. Claim 24 and 29 are amended. New claims 43-45 are added. Claims 24-25, 27-31, and 43-45 are pending.
Claim 30 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4/10/25. Claims 43-45 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse based on previously examined claims being elected by original presentation.
Claims 24-25, 27-29 and 31 are currently under consideration for patentability under 37 CFR 1.104.
Information Disclosure Statement
The information disclosure statements filed on 8/15/25 have been considered. A signed copy is enclosed.
Compliance with 37 CFR §§ 1.821—1.825
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 C.F.R. § 1.821(a)(1) and (a)(2). The amendments and sequence listing filed 10/16/25 places the application in compliance with the requirements of 37 C.F.R. §§ 1.821-1.825
Objections Withdrawn
The objection to the specification for the use of numerous trademarks on multiple pages is withdrawn in light of Applicant’s amendments thereto.
The objection to claim 24 because of the following informalities: the claims contain acronyms and/or abbreviations that should be spelled out upon first occurrence is withdrawn in light of Applicant’s amendments thereto.
Claim Rejections Withdrawn
The rejection of claim 29 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 is withdrawn in light of Applicant’s amendments thereto. The rejection of claim 26 is rendered moot by cancellation of the claim.
Claim Rejections Maintained
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
The rejection of 24-25, 27-29 and 31 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 is maintained. The rejection of claim 26 is rendered moot by cancellation of the claim. 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 directed to a synthetic ligand comprising at least two binding domains wherein each binding domain of the ligand specifically binds to the extracellular domain of a receptor polypeptide, wherein the first and second receptors do not naturally multimerize in response to binding of a naturally occurring ligand and the synthetic ligand results in multimerization of receptors and activation of intracellular signaling. The binding domains must be covalently linked through a polypeptide linker. The linker can be 2-25 amino acids long. Binding domains comprise a first and second monovalent antibody that specifically bind to the extracellular domain of a first and second cytokine receptor subunit, respectively, wherein the subunit has an intracellular domain comprising at least one JAK/STAT binding sequence, respectively. Species of the receptor subunits are described in the claims. The synthetic ligand can have a binding affinity of less than about 1x10-7 for each receptor. The monovalent antibodies can be nanobodies.
The examples demonstrate synthekines SY1, which combines binding to IFNAR2 and IL-4RA, and SY2 which combines IL-2 and IL4 binding. However, the claims are drawn to vast genera of synthetic polypeptides that comprise a vast number of monovalent antibodies that can bind to dozens of possible receptors, all of which comprise many epitopes for binding, including antibodies that may not have been discovered yet. There is even greater variation possible by the combination of these monovalent antibodies, and then even further variation considering that a linker is included. These molecules have no correlation between their structure and function. The claim requires that the synthetic ligands have functional capabilities including binding to receptors, having specific binding affinities, and creating multimerization of receptors, and modulating intracellular signaling, but the specification provides no guidance regarding which synthetic ligands are capable of the required functions. 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.)
The skilled artisan cannot envision the detailed chemical structure of the encompassed synthetic ligand 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. 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 USPQ2datl966.
Protein chemistry is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number or location of mutation will have on a protein (such as a cytokine receptor) As taught by Skolnick et al (Trends Biotechnol. 2000 Jan;18(1):34-9), sequence-based methods for predicting protein function are inadequate because of the multifunctional nature of proteins (see e.g. abstract). Further, just knowing the structure of the protein is also insufficient for prediction of functional sites (see e.g. abstract). Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cell (see e.g. page 34, right column). Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works (see e.g. page 34, right column).
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.
Further, Miosge (Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):E5189-98) teach that short of mutational studies of all possible amino acid substitutions for a protein, coupled with comprehensive
functional assays, the sheer number and diversity of missense mutations that are possible for proteins means that their functional importance must presently be addressed primarily by computational inference (see e.g. page E5189, left column). However, in a study examining some of these methods, Miosge shows that there is potential for incorrect calling of mutations (see e.g. page E5196, left column, top paragraph). The authors conclude that the discordance between predicted and actual effect of missense mutations creates the potential for many false conclusions in clinical settings where sequencing is performed to detect disease-causing mutations (see e.g. page E5195, right column, last paragraph). The findings in their study show underscore the importance of interpreting variation by direct experimental measurement of the consequences of a candidate mutation, using as sensitive and specific an assay as possible (see e.g. page E5197, left column, top paragraph). 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).
Specifically regarding the encompassed antibodies, 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 genus of antibodies that can bind receptors, and that have specific functional characteristics. 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 application, 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.
One key issue is the prediction of protein function based on sequence similarity, which could be one way to identify the functional proteins that are useful in the instant claims. Kulmanov et al (Bioinformatics, 34(4), 2018, 660–668), teach that there are key challenges for protein function prediction methods (see e.g. page 661, left column). These challenges arise from the difficulty identifying and accounting for the complex relationship between protein sequence structure and function (see e.g. page 661, left column). Despite significant progress in the past years in protein structure prediction, it still requires large efforts to predict protein structure with sufficient quality to be useful in function prediction (see e.g. page 661, left column). Another challenge is that proteins do not function in isolation. In particular higher level physiological functions that go beyond simple molecular interactions will require other proteins and cannot usually be predicted by considering a single protein in isolation (see e.g. page 661, left column). Due to these challenges it is not obvious what kinds of features should be used to predict the functions of a protein and whether they can be generated efficiently for a large number of proteins, such as the vast genus of proteins encompassed by the instant claims (see e.g. page 661, left column).
The prior art recognizes that the antigen binding by antibodies requires precise orientation of the complementarity determining region (CDR) loops in the variable domain to establish the correct contact surface. For example, Vattekatte, (PeerJ. 2020 Mar 6:8:e8408. doi: 10.7717/peerj.8408. eCollection 2020.) teach that antigen binding in heavy chain only antibodies, (HCAbs) is mediated by only three CDR loops from the single variable domain (VHH) at the N-terminus of each heavy chain, (see abstract). The Vattekatte et al further teach that the amino acid length distribution in different regions of VHH (see Fig. S7) shows diversity in CDR lengths, and that most diversity in CDR3, (see page 7 and 19). However, the prior art also recognizes that a single protein can be bound by a very large and structurally diverse genus of antibodies (i.e., there is no common structural relationship even for antibodies that bind to the same protein, epitope, or overlapping epitopes). For example, Edwards et al. (Mol Biol. 2003 Nov 14;334(1):103-18) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences, and representative of almost the entire extensive heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines), and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well (see table 2, figure 2).
Lloyd et al. (Protein Eng Des Sel. 2009 Mar;22(3):159-68. Epub 2008 Oct 29.) teach that a large majority of VH/VL germline gene segments are used in the antibody response to an antigen, even when the antibodies were selected by antigen binding, (abstract). The Lloyd et al reference further teaches that in their studies, of the 841 unselected and 5,044 selected antibodies sequenced, all but one of the 49 functional VH gene segments was observed, and that there are on average about 120 different antibodies generated per antigen (page 167, column 1). Said reference also teaches that a wide variety of VH and VL pairings further increase diversity. (page 159, column 2).
Goel et al. (J Immunol. 2004 Dec 15;173(12):7358-67) teach that three mAbs that bind to the same short (12-mer) peptide, exhibit diverse V gene usage, indicating their independent germline origin. Said reference further teaches that two of these mAbs recognize the same set of amino acid residues defining the epitope (alternate amino acid residues spread over the entire sequence), however, the relative contribution of each set of residues in the peptide showed significant variation. The reference notes that all of the mAbs do not show any kind of V gene restriction among themselves, implying variable paratope structure, despite that two of these mAbs bind to the peptide through a common set of residues. (See entire reference).
Khan et al. (J Immunol (2014) 192 (11): 5398–5405) teach that two structurally diverse germline mAbs recognizing overlapping epitopes of the same short peptide do so in different topologies, the antibodies possessing entirely different CDR sequences. Said reference teaches that unrelated mAbs structurally adjust to recognize an antigen, indicating that the primary B cell response is composed of BCRs having a high degree of structural adaptability. Said reference also teaches that the common epitope(s) also adopt distinct conformations when bound to different mAbs, with the higher degree of structural plasticity inherent to the mAbs. Said reference further teaches “It has been shown that both the framework region and the CDRs have a considerable amount of inherent conformational plasticity...Therefore, it is not surprising that distinct germline Abs recognize the same epitope by rearranging the CDR conformations. This may well have implications of Ag specificity beyond the naive BCR repertoire, because Kaji et al... .have shown in a recent report that the B cell memory can contain both germline-encoded and somatically mutated BCRs.” (See entire reference).
Poosarla et al. (Biotechnol Bioeng. 2017 June ; 114(6): 1331–1342) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Rabia, et al. (Biochem Eng J. 2018 Sep 15:137:365-374. Epub 2018 Jun 5) teach what effects mutations can have on an antibody's stability, solubility, binding affinity and binding specificity. Rabia et al. report that an increase in antibody affinity can be associated with a decrease in stability (p. 366, col. 2 last paragraph; Fig. 2). Rabia et al. thus teach that affinity and specificity are not necessarily correlated and that an increase in affinity does not indicate an increase in specificity (Fig. 3; p. 368, col. 1, section 3,1st full paragraph to col. 2, 2nd full paragraph).
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.
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:
1. Applicant has amended the claims to recite synthetic ligand polypeptide that binds to the extracellular domain of two or more cytokine receptor subunits in a non-natural combination on the surface of a cell. The claims are amended as commensurate in scope with issued claims of a Japanese patent. Support for the combinations are found in Figure 2. All of the receptors referenced were well described and characterized before the filing of the instant application, so the written description requirement is satisfied for antibodies that bind to these antigens. Therefore the written description is satisfied for synthetic ligands comprising such antibodies. The Applicant further provides specific support for activation of JAK/STAT for these combinations.
Applicant’s arguments have been fully considered and are not persuasive for the following reasons:
1. First, the examination and allowance of a patent in a foreign country is not sufficient to satisfy patentability requirements in the United States.
Second, the synthetic ligands of the instant claims are not adequately described. Applicant has defined the synthetic ligands entirely by their function, without providing either a common structure among the ligands that correlates with the required function, or a representative number of adequately described species.
For antibodies in particular, describing the antigen for the antibody is not sufficient to adequately describe the antibody itself. As stated above, 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 application, 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 the rejection is maintained.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
The rejection of claim(s) 24-25, 27-28 and 31 under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Wu et al (US 2010/0233173 A1; filed 3/5/10; published 9/16/10) is maintained. The rejection of claim 26 is rendered moot by cancellation of the claim.
The instant claims are directed to a synthetic ligand polypeptide comprising: at least two binding domains, wherein each binding domain specifically binds to the extracellular domain of a cytokine receptor polypeptide subunit expressed on the surface of a cell; wherein the first binding domain is a first monovalent antibody that specifically binds to the extracellular domain of a first cytokine receptor subunit, wherein the first cytokine receptor subunit has an intracellular domain comprising at least one JAK/STAT binding sequence; and the second binding domain is a second monovalent antibody that specifically binds to the extracellular domain of a second cytokine receptor subunit, wherein the second cytokine receptor subunit has an intracellular domain comprising at least one JAK/STAT binding sequence, wherein the first and second cytokine receptor subunits do not naturally multimerize in response to contacting the cell with a naturally occurring cytokine ligand; and wherein contacting the cell expressing the first and second cytokine receptor subunits results in multimerization of the cytokine receptor subunits and activation of a JAK/STAT- mediated signal in the cell; and wherein the first and second binding domains are covalently linked through a polypeptide linker. The linker can comprise 2-25 amino acids in length. The cytokine receptor subunits can be any of those from instant claim 26, including IL-4Ralpha and IL-2Ralpha. The synthetic ligand can have a binding affinity of at least 1x10-7 for each receptor. The monovalent antibody can be an scFv, or a nanobody. The claims also recite a pharmaceutical composition comprising the ligand.
Regarding the limitations of instant claim 24, Wu et al describe novel, multispecific epitope binding proteins capable of binding to multiple epitopes, and which comprise an Fc region of an antibody constant domain (see e.g. paragraph [0012]). The binding proteins are not found in nature (see e.g. paragraph [0012]). The multispecific epitope binding proteins can comprise 1-4 or more polypeptide chains (see e.g. paragraph [0013]). This can include 1-8 epitope binding domains, which can be antibody fragments such as scFvs, single chain diabodies, variable regions of antibodies or other epitope binding domains (see e.g. paragraph [0013]). The epitope binding domains may be linked through intervening sequences (see e.g. paragraph [0014]). The multispecific epitope binding protein can comprise a first and second polypeptide chain, wherein the protein is capable of binding at least three different epitopes, wherein the first and/or second chains comprises at least two epitope binding domains (see e.g. claim 1), and the multispecific epitope binding protein may be able to stimulate or inhibit a response in a target cell by crosslinking cell surface receptors, and can activate receptors as a consequence of crosslinking the subunits (see e.g. paragraph [0018], [0021]-[0023]). The polypeptide chains can comprise 3 or 4 separate scFvs (see e.g. claim 25). The protein specifically binds distinct cell surface receptors and inhibits or neutralizes the cell surface receptors (see e.g. claim 73). The multispecific binding protein can bind to combinations of proteins, which include IL-4R (CD123), IL-2RA (CD25), IL-5RA (CD125), IL-7RA (CD127), and interferon type I and type II receptors (see e.g. paragraph [0269]-[0271]). In one specific embodiment, the multispecific protein can be used to block dimerization of the IFNAR1 receptor to block dimerization (see e.g. paragraph [0328]). According to the instant specification, JAK/STAT pathways can be activated by IL-4R (CD123), IL-2RA (CD25), IL-5RA (CD125), IL-7RA (CD127) and IFNAR1, therefore the embodiments of the multispecific polypeptide of the reference that can stimulate these receptors by binding, would inherently activate JAK/STAT pathway (see instant specification paragraph [0058]). The polypeptide chains of the reference invention may be separated by a linker (see e.g. paragraph [0156]).
Regarding the limitations of instant claim 25, the linker can comprise 1-75 amino acids, and one particular embodiment is a linker of Gly-Gly-Gly-Gly-Ser (see e.g. paragraph [0158], wherein X is 1).
Regarding the limitations of instant claim 27, the multispecific polypeptide can have a binding affinity of less than about 1x10-7 for each receptor (see e.g. reference paragraph [0280]-[0283]).
Regarding the limitations of instant claim 28, the multispecific epitope binding proteins can comprise 1-4 or more polypeptide chains (see e.g. paragraph [0013]). This can include 1-8 epitope binding domains, which can be antibody fragments such as scFvs, single chain diabodies, variable regions of antibodies or other epitope binding domains (see e.g. paragraph [0013]).
Regarding the limitations of instant claim 31, the polypeptide of the reference may be formulated in a pharmaceutical composition (see e.g. paragraph [0421]).
Applicant’s Arguments
Applicant argues:
1. Applicant submits that the claims are not anticipated by the reference. The combinations of cytokine receptor units and activation of JAK/STAT signaling is not taught or suggested by Wu.
Applicant’s arguments have been fully considered and are not persuasive for the following reasons:
1. As stated above, Wu specifically describes multispecific epitope binding proteins capable of binding to multiple epitopes, and which comprise an Fc region of an antibody constant domain (see e.g. paragraph [0012]). The binding proteins are not found in nature (see e.g. paragraph [0012]). The multispecific epitope binding protein can comprise a first and second polypeptide chain, wherein the protein is capable of binding at least three different epitopes, wherein the first and/or second chains comprises at least two epitope binding domains (see e.g. claim 1), and the multispecific epitope binding protein may be able to stimulate or inhibit a response in a target cell by crosslinking cell surface receptors, and can activate receptors as a consequence of crosslinking the subunits (see e.g. paragraph [0018], [0021]-[0023]). The multispecific binding protein can bind to combinations of proteins, which include IL-4R (CD123), IL-2RA (CD25), IL-5RA (CD125), IL-7RA (CD127), and interferon type I and type II receptors (see e.g. paragraph [0269]-[0271]), which read on the currently amended claims. In one specific embodiment, the multispecific protein can be used to block dimerization of the IFNAR1 receptor to block dimerization (see e.g. paragraph [0328]). According to the instant specification, JAK/STAT pathways can be activated by IL-4R (CD123), IL-2RA (CD25), IL-5RA (CD125), IL-7RA (CD127) and IFNAR1, therefore the embodiments of the multispecific polypeptide of the reference that can stimulate these receptors by binding, would inherently activate JAK/STAT pathway (see instant specification paragraph [0058]). At least one combination in the currently amended claims is anticipated by Wu, and the combination of receptors would inherently activate the JAK/STAT pathway, and therefore the rejection is maintained.
In the instant case, the composition requires specific components which are all described within the Wu reference. MPEP 2131.02 states that when the species is clearly named in a reference, the species claim is anticipated no matter how many other species are additionally named. Ex parte A, 17 USPQ2d 1716 (Bd. Pat. App. & Inter. 1990) (The claimed compound was named in a reference which also disclosed 45 other compounds. The Board held that the comprehensiveness of the listing did not negate the fact that the compound claimed was specifically taught. The Board compared the facts to the situation in which the compound was found in the Merck Index, saying that “the tenth edition of the Merck Index lists ten thousand compounds. In our view, each and every one of those compounds is ‘described’ as that term is used in 35 U.S.C. § 102(a), in that publication.”). Id. at 1718. See also In re Sivaramakrishnan, 673 F.2d 1383, 213 USPQ 441 (CCPA 1982) (The claims were directed to polycarbonate containing cadmium laurate as an additive. The court upheld the Board’s finding that a reference specifically naming cadmium laurate as an additive amongst a list of many suitable salts in polycarbonate resin anticipated the claims. The applicant had argued that cadmium laurate was only disclosed as representative of the salts and was expected to have the same properties as the other salts listed while, as shown in the application, cadmium laurate had unexpected properties. The court held that it did not matter that the salt was not disclosed as being preferred, the reference still anticipated the claims and because the claim was anticipated, the unexpected properties were immaterial.). Wu specifically indicates that a combination of “one or more epitope binding domains that are specific for distinct epitopes” are anticipated (see e.g. paragraph [0016]). “One or more” generally encompasses all possible combinations the components listed in the reference. The reference discloses all combinations of the agents listed, even though each specific combination is not specifically enumerated. Furthermore, Applicant's own disclosure uses similar language that combinations of “one or more” polypeptide are envisioned (see e.g. paragraph [0011] of the instant specification). For example, the instant specification teaches synthekines engineered to bind to “combination of receptor polypeptides in the table above” (see e.g. paragraph [0059] of the instant specification). Therefore, Applicant has used similar language to identify a similar scope of possible combinations.
The rejection of claim(s) 24, 28 and 31 under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Chowdhury et al (US 2014/0348839 A1; filed 12/18/12; published 11/27/14) is maintained. The rejection of claim 26 is rendered moot by cancellation of the claim.
The instant claims are directed to a synthetic ligand polypeptide comprising: at least two binding domains, wherein each binding domain specifically binds to the extracellular domain of a cytokine receptor polypeptide subunit expressed on the surface of a cell; wherein the first binding domain is a first monovalent antibody that specifically binds to the extracellular domain of a first cytokine receptor subunit, wherein the first cytokine receptor subunit has an intracellular domain comprising at least one JAK/STAT binding sequence; and the second binding domain is a second monovalent antibody that specifically binds to the extracellular domain of a second cytokine receptor subunit, wherein the second cytokine receptor subunit has an intracellular domain comprising at least one JAK/STAT binding sequence, wherein the first and second cytokine receptor subunits do not naturally multimerize in response to contacting the cell with a naturally occurring cytokine ligand; and wherein contacting the cell expressing the first and second cytokine receptor subunits results in multimerization of the cytokine receptor subunits and activation of a JAK/STAT- mediated signal in the cell; and wherein the first and second binding domains are covalently linked through a polypeptide linker. The linker can comprise 2-25 amino acids in length. The cytokine receptor subunits can be any of those from instant claim 26, including IL-4Ralpha and IL-2Ralpha. The synthetic ligand can have a binding affinity of at least 1x10-7 for each receptor. The monovalent antibody can be an scFv, or a nanobody. The claims also recite a pharmaceutical composition comprising the ligand.
Regarding the limitations of instant claims 24, Chowdhury et al teach multispecific engineered antibodies (see e.g. abstract). The antibodies can be monovalent bispecific antibodies (see e.g. paragraph [0086]). The antibodies can be capable of binding two or more receptors, including IL-2RA, IL4R, IL5RA, IL7R, and IFNAR2 (see e.g. paragraph [0110]). The antibody can bind to two antigen molecules, and cause antigen cross-linking/ signaling, which can be regulated by the multispecific antibody concentration (see e.g. paragraph [0087]-[0088]). According to the instant specification, JAK/STAT pathways can be activated by IL-4R (CD123), IL-2RA (CD25), IL-5RA (CD125), IL-7RA (CD127) and IFNAR1, therefore the embodiments of the multispecific polypeptide of the reference that can stimulate these receptors by binding, would inherently activate JAK/STAT pathway (see instant specification paragraph [0058]). The monovalent antibody moieties can be connected to a linker (see e.g. paragraph [0082], [0094], [0253]). The polypeptide chain for the antibodies can comprise a polypeptide chain that can have the formula VD1-(X1)n-VD2-(X2)n-Fc, wherein VD1 and VD2 are the first and second variable domains, and X1 and X2 represent linkers that are a single amino acid or a polypeptide, for example a flexible linker (see e.g. reference paragraph [0082]).
Regarding the limitations of instant claim 28, Chowdhury et al teach that the antibodies can comprise scFv (see e.g. paragraph [0089], [0123]-[0126]).
Regarding the limitations of instant claim 31, the antibodies of Chowdhury et al can be present in a pharmaceutical composition (see e.g. paragraph [0261]-[0262]).
Applicant’s Arguments
Applicant argues:
1. Applicant submits that the claims are not anticipated by the reference. The combinations of cytokine receptor units and activation of JAK/STAT signaling is not taught or suggested by Chowdhury.
Applicant’s arguments have been fully considered and are not persuasive for the following reasons:
1. As stated above, Chowdhury specifically describes multispecific engineered antibodies (see e.g. abstract). The antibodies can be monovalent bispecific antibodies (see e.g. paragraph [0086]). The antibodies can be capable of binding two or more receptors, including IL-2RA, IL4R, IL5RA, IL7R, and IFNAR2 (see e.g. paragraph [0110]). The antibody can bind to two antigen molecules, and cause antigen cross-linking/ signaling, which can be regulated by the multispecific antibody concentration (see e.g. paragraph [0087]-[0088]). According to the instant specification, JAK/STAT pathways can be activated by IL-4R (CD123), IL-2RA (CD25), IL-5RA (CD125), IL-7RA (CD127) and IFNAR1, therefore the embodiments of the multispecific polypeptide of the reference that can stimulate these receptors by binding, would inherently activate JAK/STAT pathway (see instant specification paragraph [0058]). The monovalent antibody moieties can be connected to a linker (see e.g. paragraph [0082], [0094], [0253]). The polypeptide chain for the antibodies can comprise a polypeptide chain that can have the formula VD1-(X1)n-VD2-(X2)n-Fc, wherein VD1 and VD2 are the first and second variable domains, and X1 and X2 represent linkers that are a single amino acid or a polypeptide, for example a flexible linker (see e.g. reference paragraph [0082]). The combinations in the currently amended claims are anticipated by Chowdhury, and the combinations of receptors would inherently activate the JAK/STAT pathway, and therefore the rejection is maintained.
In the instant case, the composition requires specific components which are all described within the Chowdhury reference. MPEP 2131.02 states that when the species is clearly named in a reference, the species claim is anticipated no matter how many other species are additionally named. Ex parte A, 17 USPQ2d 1716 (Bd. Pat. App. & Inter. 1990) (The claimed compound was named in a reference which also disclosed 45 other compounds. The Board held that the comprehensiveness of the listing did not negate the fact that the compound claimed was specifically taught. The Board compared the facts to the situation in which the compound was found in the Merck Index, saying that “the tenth edition of the Merck Index lists ten thousand compounds. In our view, each and every one of those compounds is ‘described’ as that term is used in 35 U.S.C. § 102(a), in that publication.”). Id. at 1718. See also In re Sivaramakrishnan, 673 F.2d 1383, 213 USPQ 441 (CCPA 1982) (The claims were directed to polycarbonate containing cadmium laurate as an additive. The court upheld the Board’s finding that a reference specifically naming cadmium laurate as an additive amongst a list of many suitable salts in polycarbonate resin anticipated the claims. The applicant had argued that cadmium laurate was only disclosed as representative of the salts and was expected to have the same properties as the other salts listed while, as shown in the application, cadmium laurate had unexpected properties. The court held that it did not matter that the salt was not disclosed as being preferred, the reference still anticipated the claims and because the claim was anticipated, the unexpected properties were immaterial.). Wu specifically indicates that a combination of “one or more single chain variable fragments” are anticipated (see e.g. paragraph [0089]). “One or more” generally encompasses all possible combinations the components listed in the reference. The reference discloses all combinations of the agents listed, even though each specific combination is not specifically enumerated. Furthermore, Applicant's own disclosure uses similar language that combinations of “one or more” polypeptide are envisioned (see e.g. paragraph [0011] of the instant specification). For example, the instant specification teaches synthekines engineered to bind to “combination of receptor polypeptides in the table above” (see e.g. paragraph [0059] of the instant specification). Therefore, Applicant has used similar language to identify a similar scope of possible combinations.
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.
The rejection of claim(s) 24-25, 27-29 and 31 under 35 U.S.C. 103 as being unpatentable over Wu et al (US 2010/0233173 A1; filed 3/5/10; published 9/16/10) in view of Wesolowski et al (Med Microbiol Immunol (2009) 198:157–174) is maintained. The rejection of claim 26 is rendered moot by cancellation of the claim.
The instant claims are directed to a synthetic ligand polypeptide comprising: at least two binding domains, wherein each binding domain specifically binds to the extracellular domain of a cytokine receptor polypeptide subunit expressed on the surface of a cell; wherein the first binding domain is a first monovalent antibody that specifically binds to the extracellular domain of a first cytokine receptor subunit, wherein the first cytokine receptor subunit has an intracellular domain comprising at least one JAK/STAT binding sequence; and the second binding domain is a second monovalent antibody that specifically binds to the extracellular domain of a second cytokine receptor subunit, wherein the second cytokine receptor subunit has an intracellular domain comprising at least one JAK/STAT binding sequence, wherein the first and second cytokine receptor subunits do not naturally multimerize in response to contacting the cell with a naturally occurring cytokine ligand; and wherein contacting the cell expressing the first and second cytokine receptor subunits results in multimerization of the cytokine receptor subunits and activation of a JAK/STAT- mediated signal in the cell; and wherein the first and second binding domains are covalently linked through a polypeptide linker. The linker can comprise 2-25 amino acids in length. The cytokine receptor subunits can be any of those from instant claim 26, including IL-4Ralpha and IL-2Ralpha. The synthetic ligand can have a binding affinity of at least 1x10-7 for each receptor. The monovalent antibody can be an scFv, or a nanobody. The claims also recite a pharmaceutical composition comprising the ligand.
Regarding the limitations of instant claim 24, Wu et al describe novel, multispecific epitope binding proteins capable of binding to multiple epitopes, and which comprise an Fc region of an antibody constant domain (see e.g. paragraph [0012]). The binding proteins are not found in nature (see e.g. paragraph [0012]). The multispecific epitope binding proteins can comprise 1-4 or more polypeptide chains (see e.g. paragraph [0013]). This can include 1-8 epitope binding domains, which can be antibody fragments such as scFvs, single chain diabodies, variable regions of antibodies or other epitope binding domains (see e.g. paragraph [0013]). The epitope binding domains may be linked through intervening sequences (see e.g. paragraph [0014]). The multispecific epitope binding protein can comprise a first and second polypeptide chain, wherein the protein is capable of binding at least three different epitopes, wherein the first and/or second chains comprises at least two epitope binding domains (see e.g. claim 1), and the multispecific epitope binding protein may be able to stimulate or inhibit a response in a target cell by crosslinking cell surface receptors, and can activate receptors as a consequence of crosslinking the subunits (see e.g. paragraph [0018], [0021]-[0023]). The polypeptide chains can comprise 3 or 4 separate scFvs (see e.g. claim 25). The protein specifically binds distinct cell surface receptors and inhibits or neutralizes the cell surface receptors (see e.g. claim 73). The multispecific binding protein can bind to combinations of proteins, which include IL-4R (CD123), IL-2RA (CD25), IL-5RA (CD125), IL-7RA (CD127), and interferon type I and type II receptors (see e.g. paragraph [0269]-[0271]). In one specific embodiment, the multispecific protein can be used to block dimerization of the IFNAR1 receptor to block dimerization (see e.g. paragraph [0328]). According to the instant specification, JAK/STAT pathways can be activated by IL-4R (CD123), IL-2RA (CD25), IL-5RA (CD125), IL-7RA (CD127) and IFNAR1, therefore the embodiments of the multispecific polypeptide of the reference that can stimulate these receptors by binding, would inherently activate JAK/STAT pathway (see instant specification paragraph [0058]). The polypeptide chains of the reference invention may be separated by a linker (see e.g. paragraph [0156]).
Regarding the limitations of instant claim 25, the linker can comprise 1-75 amino acids, and one particular embodiment is a linker of Gly-Gly-Gly-Gly-Ser (see e.g. paragraph [0158], wherein X is 1).
Regarding the limitations of instant claim 27, the multispecific polypeptide can have a binding affinity of less than about 1x10-7 for each receptor (see e.g. reference paragraph [0280]-[0283]).
Regarding the limitations of instant claim 28, the multispecific epitope binding proteins can comprise 1-4 or more polypeptide chains (see e.g. paragraph [0013]). This can include 1-8 epitope binding domains, which can be antibody fragments such as scFvs, single chain diabodies, variable regions of antibodies or other epitope binding domains (see e.g. paragraph [0013]).
Regarding the limitations of instant claim 31, the polypeptide of the reference may be formulated in a pharmaceutical composition (see e.g. paragraph [0421]).
Wu does not describe the use of Nanobodies as recited in instant claim 29.
Wesolowski describes the use of single domain antibodies (sdAbs), or nanobodies, for modulating immune functions and for targeting toxins and microbes (see e.g. abstract).
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the antibodies of Wu to use Nanobodies instead of scFv molecules to increase desirable properties of the molecules. Recombinantly expressed Nanobodies (sdAbs) display several advantages as compared to single chain variable fragments (scFv) (see e.g. Wesolowski page 159, right column). The Nanobodies’ high thermal stability, high refolding capacity, and good tissue penetration in vivo make nanobodies ideally suited for various biotechnological and therapeutic applications (see e.g. Wesolowski page 159, right column). Nanobodies (sdAbs) can be readily cloned into various formats by fusion to other proteins or peptides, thereby tailoring their utility for certain diagnostic and/or therapeutic applications (see e.g. Wesolowski page 159, right column). Furthermore, Tandem cloning of two identical Nanobodies (sdAbs) connected by a linker peptide yields a bivalent reagent with higher avidity for the antigen (see e.g. Wesolowski page 160, left column). It would be expected, absent evidence to the contrary, that substitution of Nanobodies (sdAbs) for the scFv of Wu would produce a molecule that possesses these advantageous qualities. The advantages of higher avidity for antigen, high thermal stability, high refolding capacity, and good tissue penetration provides the motivation to make the aforementioned modification of the antibody of Wu et al, based on the teachings of Wesolowski et al, with a reasonable expectation of success.
It would have been obvious to one with ordinary skill in the art, at the time of the invention, to use nanobodies, or sdAbs, in the molecule of Wu due to the advantageous properties of nanobodies. The Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. Nanobodies (sdAbs) are a known antibody fragment with known advantageous properties as stated above (see Wesolowski et al, page 159-160). The use of Nanobodies as antibody fragments in bivalent molecules are encompassed in a known variation or principle in the art, as shown by Wesolowski et al, and therefore using Nanobodies (sdAbs) in the molecule of Wu et al would have been predictable to one of ordinary skill in the art. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Applicant’s Arguments
Applicant argues:
1. Applicant submits that the claims are not anticipated by the reference. The combinations of cytokine receptor units and activation of JAK/STAT signaling is not taught or suggested by Wu.
2. Applicant submits that Wesolowski does not teach specific combinations of cytokine receptor subunits that do not naturally multimerize in response to contacting the cell with a naturally occurring cytokine ligand.
Applicant’s arguments have been fully considered and are not persuasive for the following reasons:
1. As stated above, Wu specifically describes multispecific epitope binding proteins capable of binding to multiple epitopes, and which comprise an Fc region of an antibody constant domain (see e.g. paragraph [0012]). The binding proteins are not found in nature (see e.g. paragraph [0012]). The multispecific epitope binding protein can comprise a first and second polypeptide chain, wherein the protein is capable of binding at least three different epitopes, wherein the first and/or second chains comprises at least two epitope binding domains (see e.g. claim 1), and the multispecific epitope binding protein may be able to stimulate or inhibit a response in a target cell by crosslinking cell surface receptors, and can activate receptors as a consequence of crosslinking the subunits (see e.g. paragraph [0018], [0021]-[0023]). The multispecific binding protein can bind to combinations of proteins, which include IL-4R (CD123), IL-2RA (CD25), IL-5RA (CD125), IL-7RA (CD127), and interferon type I and type II receptors (see e.g. paragraph [0269]-[0271]), which read on the currently amended claims. In one specific embodiment, the multispecific protein can be used to block dimerization of the IFNAR1 receptor to block dimerization (see e.g. paragraph [0328]). According to the instant specification, JAK/STAT pathways can be activated by IL-4R (CD123), IL-2RA (CD25), IL-5RA (CD125), IL-7RA (CD127) and IFNAR1, therefore the embodiments of the multispecific polypeptide of the reference that can stimulate these receptors by binding, would inherently activate JAK/STAT pathway (see instant specification paragraph [0058]). The combinations in the currently amended claims are anticipated by Wu, and the combinations of receptors would inherently activate the JAK/STAT pathway, and therefore the rejection is maintained.
In the instant case, the composition requires specific components which are all described within the Wu reference. MPEP 2131.02 states that when the species is clearly named in a reference, the species claim is anticipated no matter how many other species are additionally named. Ex parte A, 17 USPQ2d 1716 (Bd. Pat. App. & Inter. 1990) (The claimed compound was named in a reference which also disclosed 45 other compounds. The Board held that the comprehensiveness of the listing did not negate the fact that the compound claimed was specifically taught. The Board compared the facts to the situation in which the compound was found in the Merck Index, saying that “the tenth edition of the Merck Index lists ten thousand compounds. In our view, each and every one of those compounds is ‘described’ as that term is used in 35 U.S.C. § 102(a), in that publication.”). Id. at 1718. See also In re Sivaramakrishnan, 673 F.2d 1383, 213 USPQ 441 (CCPA 1982) (The claims were directed to polycarbonate containing cadmium laurate as an additive. The court upheld the Board’s finding that a reference specifically naming cadmium laurate as an additive amongst a list of many suitable salts in polycarbonate resin anticipated the claims. The applicant had argued that cadmium laurate was only disclosed as representative of the salts and was expected to have the same properties as the other salts listed while, as shown in the application, cadmium laurate had unexpected properties. The court held that it did not matter that the salt was not disclosed as being preferred, the reference still anticipated the claims and because the claim was anticipated, the unexpected properties were immaterial.). Wu specifically indicates that a combination of “one or more epitope binding domains that are specific for distinct epitopes” are anticipated (see e.g. paragraph [0016]). “One or more” generally encompasses all possible combinations the components listed in the reference. The reference discloses all combinations of the agents listed, even though each specific combination is not specifically enumerated. Furthermore, Applicant's own disclosure uses similar language that combinations of “one or more” polypeptide are envisioned (see e.g. paragraph [0011] of the instant specification). For example, the instant specification teaches synthekines engineered to bind to “combination of receptor polypeptides in the table above” (see e.g. paragraph [0059] of the instant specification). Therefore, Applicant has used similar language to identify a similar scope of possible combinations.
2. Applicant is arguing the separate teachings of the references without considering the teachings as a whole. As stated in MPEP 2145, One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Where a rejection of a claim is based on two or more references, a reply that is limited to what a subset of the applied references teaches or fails to teach, or that fails to address the combined teaching of the applied references may be considered to be an argument that attacks the reference(s) individually.
The rejection of claim(s) 24, 28-29 and 31 under 35 U.S.C. 103 as being unpatentable over Chowdhury et al (US 2014/0348839 A1; filed 12/18/12; published 11/27/14) in view of Wesolowski et al (Med Microbiol Immunol (2009) 198:157–174) is maintained. The rejection of claim 26 is rendered moot by cancellation of the claim.
The instant claims are directed to a synthetic ligand polypeptide comprising: at least two binding domains, wherein each binding domain specifically binds to the extracellular domain of a cytokine receptor polypeptide subunit expressed on the surface of a cell; wherein the first binding domain is a first monovalent antibody that specifically binds to the extracellular domain of a first cytokine receptor subunit, wherein the first cytokine receptor subunit has an intracellular domain comprising at least one JAK/STAT binding sequence; and the second binding domain is a second monovalent antibody that specifically binds to the extracellular domain of a second cytokine receptor subunit, wherein the second cytokine receptor subunit has an intracellular domain comprising at least one JAK/STAT binding sequence, wherein the first and second cytokine receptor subunits do not naturally multimerize in response to contacting the cell with a naturally occurring cytokine ligand; and wherein contacting the cell expressing the first and second cytokine receptor subunits results in multimerization of the cytokine receptor subunits and activation of a JAK/STAT- mediated signal in the cell; and wherein the first and second binding domains are covalently linked through a polypeptide linker. The linker can comprise 2-25 amino acids in length. The cytokine receptor subunits can be any of those from instant claim 26, including IL-4Ralpha and IL-2Ralpha. The synthetic ligand can have a binding affinity of at least 1x10-7 for each receptor. The monovalent antibody can be an scFv, or a nanobody. The claims also recite a pharmaceutical composition comprising the ligand.
Regarding the limitations of instant claims 24 and 26, Chowdhury et al teach multispecific engineered antibodies (see e.g. abstract). The antibodies can be monovalent bispecific antibodies (see e.g. paragraph [0086]). The antibodies can be capable of binding two or more receptors, including IL-2RA, IL4R, IL5RA, IL7R, and IFNAR2 (see e.g. paragraph [0110]). The antibody can bind to two antigen molecules, and cause antigen cross-linking/ signaling, which can be regulated by the multispecific antibody concentration (see e.g. paragraph [0087]-[0088]). According to the instant specification, JAK/STAT pathways can be activated by IL-4R (CD123), IL-2RA (CD25), IL-5RA (CD125), IL-7RA (CD127) and IFNAR1, therefore the embodiments of the multispecific polypeptide of the reference that can stimulate these receptors by binding, would inherently activate JAK/STAT pathway (see instant specification paragraph [0058]). The monovalent antibody moieties can be connected to a linker (see e.g. paragraph [0082], [0094], [0253]). The polypeptide chain for the antibodies can comprise a polypeptide chain that can have the formula VD1-(X1)n-VD2-(X2)n-Fc, wherein VD1 and VD2 are the first and second variable domains, and X1 and X2 represent linkers that are a single amino acid or a polypeptide, for example a flexible linker (see e.g. reference paragraph [0082]).
Regarding the limitations of instant claim 28, Chowdhury et al teach that the antibodies can comprise scFv (see e.g. paragraph [0089], [0123]-[0126]).
Regarding the limitations of instant claim 31, the antibodies of Chowdhury et al can be present in a pharmaceutical composition (see e.g. paragraph [0261]-[0262]).
Wu does not describe the use of Nanobodies as recited in instant claim 29.
Wesolowski describes the use of single domain antibodies (sdAbs), or Nanobodies, for modulating immune functions and for targeting toxins and microbes (see e.g. abstract).
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the antibodies of Chowdhury et al to use Nanobodies instead of scFv molecules to increase desirable properties of the molecules. Recombinantly expressed Nanobodies (sdAbs) display several advantages as compared to single chain variable fragments (scFv) (see e.g. Wesolowski page 159, right column). The Nanobodies’ high thermal stability, high refolding capacity, and good tissue penetration in vivo make nanobodies ideally suited for various biotechnological and therapeutic applications (see e.g. Wesolowski page 159, right column). Nanobodies (sdAbs) can be readily cloned into various formats by fusion to other proteins or peptides, thereby tailoring their utility for certain diagnostic and/or therapeutic applications (see e.g. Wesolowski page 159, right column). Furthermore, Tandem cloning of two identical Nanobodies (sdAbs) connected by a linker peptide yields a bivalent reagent with higher avidity for the antigen (see e.g. Wesolowski page 160, left column). It would be expected, absent evidence to the contrary, that substitution of Nanobodies (sdAbs) for the scFv of Chowdhury et al would produce a molecule that possesses these advantageous qualities. The advantages of higher avidity for antigen, high thermal stability, high refolding capacity, and good tissue penetration provides the motivation to make the aforementioned modification of the antibody of Chowdhury et al, based on the teachings of Wesolowski et al, with a reasonable expectation of success.
It would have been obvious to one with ordinary skill in the art, at the time of the invention, to use nanobodies, or sdAbs, in the molecule of Wu due to the advantageous properties of nanobodies. The Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. Nanobodies (sdAbs) are a known antibody fragment with known advantageous properties as stated above (see Wesolowski et al, page 159-160). The use of Nanobodies as antibody fragments in bivalent molecules are encompassed in a known variation or principle in the art, as shown by Wesolowski et al, and therefore using Nanobodies (sdAbs) in the molecule of Chowdhury et al would have been predictable to one of ordinary skill in the art. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Applicant’s Arguments
Applicant argues:
1. Applicant submits that the claims are not anticipated by the reference. The combinations of cytokine receptor units and activation of JAK/STAT signaling is not taught or suggested by Chowdhury.
2. Applicant submits that Wesolowski does not teach specific combinations of cytokine receptor subunits that do not naturally multimerize in response to contacting the cell with a naturally occurring cytokine ligand.
Applicant’s arguments have been fully considered and are not persuasive for the following reasons:
1. As stated above, Chowdhury specifically describes multispecific engineered antibodies (see e.g. abstract). The antibodies can be monovalent bispecific antibodies (see e.g. paragraph [0086]). The antibodies can be capable of binding two or more receptors, including IL-2RA, IL4R, IL5RA, IL7R, and IFNAR2 (see e.g. paragraph [0110]). The antibody can bind to two antigen molecules, and cause antigen cross-linking/ signaling, which can be regulated by the multispecific antibody concentration (see e.g. paragraph [0087]-[0088]). According to the instant specification, JAK/STAT pathways can be activated by IL-4R (CD123), IL-2RA (CD25), IL-5RA (CD125), IL-7RA (CD127) and IFNAR1, therefore the embodiments of the multispecific polypeptide of the reference that can stimulate these receptors by binding, would inherently activate JAK/STAT pathway (see instant specification paragraph [0058]). The monovalent antibody moieties can be connected to a linker (see e.g. paragraph [0082], [0094], [0253]). The polypeptide chain for the antibodies can comprise a polypeptide chain that can have the formula VD1-(X1)n-VD2-(X2)n-Fc, wherein VD1 and VD2 are the first and second variable domains, and X1 and X2 represent linkers that are a single amino acid or a polypeptide, for example a flexible linker (see e.g. reference paragraph [0082]). The combinations in the currently amended claims are anticipated by Chowdhury, and the combinations of receptors would inherently activate the JAK/STAT pathway, and therefore the rejection is maintained.
In the instant case, the composition requires specific components which are all described within the Chowdhury reference. MPEP 2131.02 states that when the species is clearly named in a reference, the species claim is anticipated no matter how many other species are additionally named. Ex parte A, 17 USPQ2d 1716 (Bd. Pat. App. & Inter. 1990) (The claimed compound was named in a reference which also disclosed 45 other compounds. The Board held that the comprehensiveness of the listing did not negate the fact that the compound claimed was specifically taught. The Board compared the facts to the situation in which the compound was found in the Merck Index, saying that “the tenth edition of the Merck Index lists ten thousand compounds. In our view, each and every one of those compounds is ‘described’ as that term is used in 35 U.S.C. § 102(a), in that publication.”). Id. at 1718. See also In re Sivaramakrishnan, 673 F.2d 1383, 213 USPQ 441 (CCPA 1982) (The claims were directed to polycarbonate containing cadmium laurate as an additive. The court upheld the Board’s finding that a reference specifically naming cadmium laurate as an additive amongst a list of many suitable salts in polycarbonate resin anticipated the claims. The applicant had argued that cadmium laurate was only disclosed as representative of the salts and was expected to have the same properties as the other salts listed while, as shown in the application, cadmium laurate had unexpected properties. The court held that it did not matter that the salt was not disclosed as being preferred, the reference still anticipated the claims and because the claim was anticipated, the unexpected properties were immaterial.). Wu specifically indicates that a combination of “one or more single chain variable fragments” are anticipated (see e.g. paragraph [0089]). “One or more” generally encompasses all possible combinations the components listed in the reference. The reference discloses all combinations of the agents listed, even though each specific combination is not specifically enumerated. Furthermore, Applicant's own disclosure uses similar language that combinations of “one or more” polypeptide are envisioned (see e.g. paragraph [0011] of the instant specification). For example, the instant specification teaches synthekines engineered to bind to “combination of receptor polypeptides in the table above” (see e.g. paragraph [0059] of the instant specification). Therefore, Applicant has used similar language to identify a similar scope of possible combinations.
2. Applicant is arguing the separate teachings of the references without considering the teachings as a whole. As stated in MPEP 2145, One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Where a rejection of a claim is based on two or more references, a reply that is limited to what a subset of the applied references teaches or fails to teach, or that fails to address the combined teaching of the applied references may be considered to be an argument that attacks the reference(s) individually.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
The provisional rejection of claims 24-25, 27-29 and 31 on the ground of nonstatutory double patenting as being unpatentable over claims 1-17, 19, 21, 23, and 43 of copending Application No. 18/835,511 (reference application) is maintained. The rejection of claim 26 is rendered moot by cancellation of the claim.
Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant claims are directed to a synthetic ligand polypeptide comprising: at least two binding domains, wherein each binding domain specifically binds to the extracellular domain of a cytokine receptor polypeptide subunit expressed on the surface of a cell; wherein the first binding domain is a first monovalent antibody that specifically binds to the extracellular domain of a first cytokine receptor subunit, wherein the first cytokine receptor subunit has an intracellular domain comprising at least one JAK/STAT binding sequence; and the second binding domain is a second monovalent antibody that specifically binds to the extracellular domain of a second cytokine receptor subunit, wherein the second cytokine receptor subunit has an intracellular domain comprising at least one JAK/STAT binding sequence, wherein the first and second cytokine receptor subunits do not naturally multimerize in response to contacting the cell with a naturally occurring cytokine ligand; and wherein contacting the cell expressing the first and second cytokine receptor subunits results in multimerization of the cytokine receptor subunits and activation of a JAK/STAT- mediated signal in the cell; and wherein the first and second binding domains are covalently linked through a polypeptide linker. The linker can comprise 2-25 amino acids in length. The cytokine receptor subunits can be any of those from instant claim 26, including IL-4Ralpha and IL-2Ralpha. The synthetic ligand can have a binding affinity of at least 1x10-7 for each receptor. The monovalent antibody can be an scFv, or a nanobody. The claims also recite a pharmaceutical composition comprising the ligand.
The copending application recites an engineered polypeptide comprising a single chain bispecific ligand wherein first specificity is to IFNAR1 and a second specificity is to IFNAR2, and wherein the engineered polypeptide is a cytokine agonist (see e.g. copending claim 1). The ligands can comprise a first and second nanobody (see e.g. copending claim 2). Several specific species are presented in copending claims 3-8. The single chain bispecific ligand can be a dimerizing ligand for an IFNAR1/IFNAR2 receptor heterodimer (see e.g. copending claim 9). The engineered polypeptide can be capable of inducing STAT phosphorylation (see e.g. copending claim 10). The first nanobody and second nanobody can be linked by a peptide linker (see e.g. copending claim 19). The engineered polypeptide can be present in a pharmaceutical composition (see e.g. copending claim 23). The engineered polypeptide can comprise an scFv and a nanobody (see e.g. copending claim 43).
Instant claims 24, 26, 29, and 31 are anticipated by the copending application. Regarding claims 25, 27, and 28,
It would have been prima facie obvious to one having ordinary skill before the effective filing date of the claimed invention, to optimize the engineered polypeptide to reach the instant synthetic ligand comprising scFv for each antibody, a specific affinity for the antibody, and a range of lengths for the polypeptide linker in order to make the synthetic ligand as efficacious as possible. The MPEP states the following: “[W}here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller. 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson. 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc, v. Biocraft Laboratories Inc.. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert, denied, 493 U.S. 975 (1989); In re Kulling. 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler. 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). The copending application recites antibody fragments, and peptide linkers within the claims. All of the differences between the instant claims and the copending application fall within a known variation or principle in the art regarding construction of polypeptide ligands. The Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. Thus, the copending invention elements as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Applicant’s Arguments
Applicant argues:
1. Applicant submits that as set forth in MPEP 804, if a provisional nonstatutory obviousness-type double patenting rejection is the only rejection remaining in the earlier filed of the two pending applications, the examiner should withdraw that rejection and permit the earlier filed application to issue as a patent without a terminal disclaimer. The present application is the earlier filed application and therefore the rejection should be withdrawn.
Applicant’s arguments have been fully considered and are not persuasive for the following reasons:
1. MPEP 1490 states that if the provisional nonstatutory double patenting rejections in both applications are the only rejections remaining in those applications, the examiner should then withdraw the provisional rejection in the earlier-filed application thereby permitting that application to issue without need of a terminal disclaimer. However, the nonstatutory double patenting rejection is not the only rejection remaining and therefore the rejection is maintained.
It is strongly advised that Applicants file any Terminal Disclaimer by using eTerminalDisclaimer (http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp) in EFS-Web. The new eTerminal Disclaimer provides applicants with many advantages and promotes greater efficiency in the patent examination process. This web-based eTerminal Disclaimer can be filled out completely online through web-screens and no EFS-Web fillable forms are required. eTerminal Disclaimers are auto-processed and approved immediately upon submission if the request meets all of the requirements. This is especially important for a Terminal Disclaimer filed after final.
Fees must be paid immediately which will then provide users more financial flexibility. A paper filed Terminal Disclaimer requires a fee but does not guarantee a Terminal Disclaimer approval. Each eTerminal Disclaimer filed requires a single terminal disclaimer fee, but can include up to 50 “reference applications” and 50 “prior patents”.
See http://www.uspto.gov/patents/process/file/efs/guidance/eTD-QSG.pdf for instructions. For assistance with filing an eTerminal Disclaimer, or to suggest improvements, please call the Patent Electronic Business Center at 866-217-9197 (toll free) or send an email to EBC@uspto.gov.
Conclusion
No claim is allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDREA MCCOLLUM whose telephone number is (571)272-4002. The examiner can normally be reached 9:00 AM to 6:00 PM EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, VANESSA FORD can be reached at (571)272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ANDREA K MCCOLLUM/Examiner, Art Unit 1674
/BRIAN GANGLE/Primary Examiner, Art Unit 1645