Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on February 21, 2026 has been entered.
Response to Amendment
Amendment filed February 21, 2026 has been entered.
Claims 53-63 are pending. Claims 1-52 are canceled. Claims 53-63 are examined.
Double Patenting Rejections:
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 obviousness-type 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); and 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 a nonstatutory double patenting ground provided the conflicting application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement.
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
Claims 53-63 are rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 1-9 of US 9,993,552 issued 12 June 2018, the ‘552 patent.
Although the conflicting claims are not identical, they are not patentably distinct from each other for the following reasons.
The claims of the instant application are directed to a formulation comprising: (a) a single domain antigen binding (SDAB) molecule at a concentration from about 0.1 mg/mL to about 350 mg/mL, comprising one or more single domain molecules, wherein at least one of the single domain molecule binds to a serum protein; (b) a lyoprotectant; and (c) a histidine buffer at a concentration about 5 to about 50 mM, such that the pH of the formulation is about 5.0 to 7.5 (Claim 31). Claim 32 recites the limitation that the serum protein is HAS; claim 33 recites the further limitation that the at least one single domain molecule that binds to HSA comprises three CDRs, wherein CDR1 has the amino acid sequence SFGMS (SEQ ID NO: 5), or a variant thereof, CDR2 has the amino acid sequence SISGSGSDTLYADSVKG (SEQ ID NO: 6), or a variant thereof, and CDR3 has the amino acid sequence GGSLSR (SEQ ID NO: 7), or a variant thereof. These claims significantly overlap the subject matter of Claim 1 of the issued patent which is directed to a formulation comprising: (a) a single domain antigen binding (SDAB) molecule at a concentration from about 0.1 mg/mL to about 350 mg/mL, comprising one or more single domain molecules, wherein at least one of the single domain molecule binds to human serum albumin (HSA) and comprises three CDRs having the amino sequences: SFGMS (SEQ ID NO: 5) (CDR1), SISGSGSDTLYADSVKG (SEQ ID NO: 6) (CDR2) and GGSLSR (SEQ ID NO: 7) (CDR3); (b) a lyoprotectant; and (c) a histidine buffer at a concentration about 5 to about 50 mM, such that the pH of the formulation is about 5.0 to 7.5.
Applicant request that the rejection be held in abeyance until allowable subject matter is agreed upon. The rejection is maintained.
35 U.S.C. § 112, First Paragraph
The following is a quotation of the first paragraph of 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 following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim limitation “therapeutic agent comprises a means for binding to human serum albumin” invokes 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. However, the written description fails to disclose the corresponding structure, material, or acts for performing the entire claimed function and to clearly link the structure, material, or acts to the function. The specification does not limit the term and the term encompass generic limitations. Therefore, the claim is indefinite and is rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph.
Applicant may:
(a) Amend the claim so that the claim limitation will no longer be interpreted as a limitation under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph;
(b) Amend the written description of the specification such that it expressly recites what structure, material, or acts perform the entire claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(c) Amend the written description of the specification such that it clearly links the structure, material, or acts disclosed therein to the function recited in the claim, without introducing any new matter (35 U.S.C. 132(a)).
If applicant is of the opinion that the written description of the specification already implicitly or inherently discloses the corresponding structure, material, or acts and clearly links them to the function so that one of ordinary skill in the art would recognize what structure, material, or acts perform the claimed function, applicant should clarify the record by either:
(a) Amending the written description of the specification such that it expressly recites the corresponding structure, material, or acts for performing the claimed function and clearly links or associates the structure, material, or acts to the claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(b) Stating on the record what the corresponding structure, material, or acts, which are implicitly or inherently set forth in the written description of the specification, perform the claimed function. For more information, see 37 CFR 1.75(d) and MPEP §§ 608.01(o) and 2181.
Applicants argue that the specification describes structures having the claimed function of binding to human serum albumin (HAS) (specification page 10, lines 17-24) for means plus function. However the specification is discussing a specific SDAB that bind has of SEQ ID NO: but does not limit to the specific SDAB with SEQ ID NO:. Claims encompass generically any generic therapeutic agent that binds HSA.
Scope of Enablement
Claims 53-63 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for a therapeutic agent comprising three CDRs having the amino acid sequences of SEQ ID NOs:5-7 or 2-4 and have a variable region having the amino acid sequence from about amino acids 125-239 of SEQ ID NO:1 does not reasonably provide enablement for the full scope of the variants disclosed in the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The claims are drawn to a formulation comprising a generic therapeutic agent by name only at specific concentration. The claims are drawn to generic therapeutic agent comprising polypeptide comprising heavy chain variable domain CDRs comprising three CDRs corresponding to SEQ ID NO: which encompass variants because the term “corresponds” encompass variability in the SEQ ID NO:. Thus, the claims are directed to a plurality of therapeutic agent whose structure may exhibit a tremendous number of variants in the CDRs which bind human serum albumin (HSA) The generic therapeutic agent encompass any molecule that binds the HAS.
The state of the art is such that many molecules bind the human serum albumin including drugs as well as non-specific binding (Ghuman, 2005). The state of the prior art is such that it is well established in the art that the formation of an intact antigen binding site of antibodies routinely requires the association of the complete heavy and light chain variable regions each of which consists of three CDRs or hypervariable regions, which provide the majority of the contact residues for the binding of the antibody to its target epitope (Paul, Fundamental Immunology, 3r~ Edition, 1993, pp. 292-295, under the heading "Fv Structure and Diversity in Three Dimensions"). The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (Paul, page 293, first column, lines 3-8 and line 31 to column 2, line 9 and lines 27-30).
Despite the absence of a light chain, it is apparent that the same is true of the single domain antibody. The amino acid sequence and conformation of “heavy" chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the parent immunoglobulin; yet the claims are directed to a genus of single domain antibodies that comprise CDRs having substantially different structures and variable regions having substantially different structures.
Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al (Proc. Natl. Acad. Sci.USA, 79(6):1979-1983, March 1982). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function. Colman P. M. (Research in Immunology, 145:33-36, 1994) teaches that even a very conservative substitution may abolish binding or may have very little effect on the binding affinity (see pg. 35, top of left column and pg. 33, right column).
The importance of the residues within the CDRs of the single-domain antibody is no different; although considerably less information is available as to the specific effects of amino acid sequence alterations within the structure of the single-domain antibody, it is expected that even minor changes may drastically alter the specificity of the antibody in an unpredictable manner.
The specification teaches formulations comprising the antibody ATN-103, a single domain antibody comprising the amino acid sequence of SEQ ID NO:1 [paragraphs 0025, 0028, Figure 30, paragraph 0094, Examples 1, 5, and 9]. However, insufficient guidance is presented as to how to construct an antibody that comprises three CDRs, one or more of which have an amino acid sequence that differs by 1-2 amino acid substitutions from SEQ ID NOs:5-7 or 2-4 and comprising a variable region that differs by up to 10 amino acids from a variable region having the amino acid sequence from about amino acids SEQ ID NO:11-12, single domain molecules having at least 85% amino acid identity relative to the amino acid sequence shown in SEQ ID NO: 1, and still retain the required biological activity of binding. Insufficient guidance is presented as to how to construct an antibody that comprises three CDRs variants and still retain the required biological activity of binding. Insufficient guidance is presented as to how to construct an antibody that comprises three CDRs variants and still retain the required biological activity of binding.
Due to the large quantity of experimentation necessary to determine which residues must be conserved in the variable regions of the claimed single domain antibodies in order to maintain the requisite biological activity, the lack of direction/guidance presented in the specification regarding same, the absence of sufficient working examples directed to same, the complex nature of the invention, the state of the prior art establishing that even minor changes in the amino acid sequence of an antibody could change the binding characteristics, and the breadth of the claims, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention in its full scope.
Applicants argue that the specification describes structures having the claimed function of binding to human serum albumin (HAS) (specification page 10, lines 17-24) for means plus function. However the specification is discussing a specific SDAB that bind has of SEQ ID NO: but does not limit to the specific SDAB with SEQ ID NO:. Claims encompass generically any generic therapeutic agent that binds HSA.
Written Description
Claims 53-63 are rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement. The claim (s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection, rather than an enablement rejection under 35 U.S.C. 112, first paragraph.
The claims are drawn to therapeutic agent comprising CDRs comprising three CDRs of heavy chain which corresponds to the SEQ ID NO:. Thus, the claims are directed to a plurality of therapeutic agent whose structure may exhibit a tremendous number of variants in the CDRs because the term “correspond” encompasses changes to the sequence.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. “[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69).
Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341 (Fed. Cir. 2011) and AbbVie Deutschland GmbH v. Janssen Biotechnology, Ltd. 759 F.3d 1285 (Fed. Cir. 2014) provide holding against generic claims to antibodies whose structure cannot be envisioned from the specific species of structure provided.
A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, as there is in the instant claims, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species.
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), it is noted that to show invention, a patentee must convey in its disclosure that is “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358). Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361). An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361). Most significant to the present case, the Court held that the idea that written description of an antibody can be satisfied by the disclosure of a newly-characterized antigen “flouts basic legal principles of the written description requirement” as it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen… And Congress has not created a special written description requirement for antibodies” (Amgen at page 1362).
In the instant case, for example, claims encompass therapeutic agents with changes to the CDRs. Thus, as in Amgen, the claims attempt to describe a genus of SDABs by describing something that is not an SDAB, i.e. the protein to which the SDAB binds.
The specification discloses SDAB of the formulation as ATN-103, comprising the amino acid sequence of SEQ ID NO:1; the disclosure of a single disclosed species may provide an adequate written description of a genus when the species disclosed is representative of the genus. However, the present claims encompass numerous species that are not further described. The instant disclosure, including the claims fail to disclose a representative number of species falling with the scope of the genus or structural common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus. The specification does not provide sufficient written description as to the structural features of the claimed genus of antibodies and the correlation between the structure and function of the genus of antibodies, such as residues that are essential for antigen binding.
It has been well known that minor structural differences even among structurally related compounds can result in substantially different biology, expression and activities. Based on the instant disclosure one of skill in the art would not know which residues are essential, which residues are non-essential and what particular sequence lengths identify essential sequences for identifying an antibody that binds to HSA and TNF and encompassed by the claimed specificity of function. Mere idea of function is insufficient for written description; isolation and characterization at a minimum are required.
Skolnick, et al. (Trends in Biotechnology, 2000. Vol. 18, pages 34-39) teach that the skilled artisan is well aware that assigning functional activities for any particular protein or protein family based on sequence homology is inaccurate, in part because of the multifunctional nature of proteins (e.g., “Abstract” and “Sequence-based approaches to function prediction”, page 34). Even in situations where there is some confidence of a similar overall structure between two proteins, only experimental research can confirm the artisan’s best guess as to function of the structurally related protein (see in particular “Abstract” and Box 2).
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations 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. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs but also framework region, may dramatically affect antigen-binding function as evidenced by MacCallum, et al. (Journal of Molecular Biology, 1996. Vol. 262, pages 732-745) who analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts (see page 733, right column) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left column).
The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site is underscored by Casset, et al. (Biochemical and Biophysical Research Communications, 2003. Vol. 307, pages 198-205) which constructed a peptide mimetic of an anti-CD4 monoclonal antibody binding site by rational design and the peptide was designed with 27 residues formed by residues from 5 CDRs (see entire document). Casset et al. also states that although CDR H3 is at the center of most if not all antigen interactions, clearly other CDRs play an important role in the recognition process (page 199, left column) and this is demonstrated in this work by using all CDRs except L2 and additionally using a framework residue located just before the H3 (see page 202, left column). Vajdos, et al. (Journal of Molecular Biology, 2002. Vol. 320, pages 415-428) additionally state that antigen binding is primarily mediated by the CDRs more highly conserved framework segments which connect the CDRs are mainly involved in supporting the CDR loop conformations and in some cases framework residues also contact antigen (page 416, left column). Wu, et al. (Journal of Molecular Biology, 1999. Vol. 294, pages 151-162) state that it is difficult to predict which framework residues serve a critical role in maintaining affinity and specificity due in part to the large conformational change in antibodies that accompany antigen binding (page 152 left column) but certain residues have been identified as important for maintaining conformation.
A “representative number of species" means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). AbbVie [AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc., 111 USPQ2d 1780, at 1788 (Fed. Cir. 2014)] held (at 1790) that, “Although the number of the described
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appears high quantitatively, the described
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are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the
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genus See Ariad, 598 F.3d at 1351 (“[No] bright-line rules govern[] the number of
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that must be disclosed to describe a
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genus claim, as this number necessarily changes with each invention, and it changes with progress in a field.”).
Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The “structural features common to the members of the genus” needed for one of skill in the art to 'visualize or recognize' the members of the genus takes into account the state of the art at the time of the invention.
Here, the claims are directed to a genus of SDABs molecules are defined by their desired binding to an antigen and function of such binding.
It is well-known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope. For example, Lloyd et al. taught that over hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Protein Engineering, Design & Selection 2009, 22:159-168; see, e.g., Discussion). The genus of antibodies as claimed includes variations in the polypeptide which affect CDRs function as antibodies. Mutation of even a single amino acid residue affects antigen binding. Wu, et al. (Journal of Molecular Biology, 1999. Vol. 294, pages 151-162,) state that it is difficult to predict which framework residues serve a critical role in maintaining affinity and specificity due in part to the large conformational change in antibodies that accompany antigen binding (page 152 left column) but certain residues have been identified as important for maintaining conformation. Additionally, even minor changes in the amino acid sequences of the heavy and light variable regions, including framework, may dramatically affect antigen-binding function as evidenced by MacCallum, et al. (Journal of Molecular Biology, 1996. Vol. 262, pages 732-745) who analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts (see page 733, right column) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left column). The specification does not disclose an antibody with changes to framework which have the claimed functional characteristics. Thus, applicant was not in possession of the broad genus of antibodies as claimed.
Given the well-known high level of polymorphism of immunoglobulins / antibodies and SDABs, the skilled artisan would not have been in possession of the vast repertoire of SDABs and the unlimited number of SDABs encompassed by the claimed invention; one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genera. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genera.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
Applicants argue that the specification describes structures having the claimed function of binding to human serum albumin (HAS) (specification page 10, lines 17-24) for means plus function. However the specification is discussing a specific SDAB that bind has of SEQ ID NO: but does not limit to the specific SDAB with SEQ ID NO:. Claims encompass generically any generic therapeutic agent that binds HSA.
35 U.S.C. § 103:
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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 under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Claims 53-63 are rejected under 35 U.S.C. 103(a) as being unpatentable over Beirnaert et al. (WO 2006/122787) in view of Goldstein et al. (US 20090306348, priority claimed to 15 February 2007, the ‘348 reference).
The cited references establish the following fact pattern:
Beirnaert et al (‘787 reference) teach a single domain antibody which is capable of binding human serum albumin (abstract and page 4, lines 18-22).
The SDAB comprises the following anti-serum nanobody CDRs[Wingdings font/0x4C]pages 12-13)
SEQ ID NO:10, which is 100% identical to the instantly claimed SEQ ID NO:5
SEQ ID NO:24, which is 100% identical to the instantly claimed SEQ ID NO:6
SEQ ID NO:38, which is 100% identical to the instantly claimed SEQ ID NO:7
(See results in SCORE)
The reference also teaches that CDR1 may differ by 1 or 2 amino acid substitutions from SEQ ID NO:10 (page 6, lines 28-31), CDR2 may differ by 1 or 2 amino acid substitutions from SEQ ID NO:24 (page 7, lines 1-7) and CDR3 may differ by 1 or 2 amino acid substitutions from SEQ ID NO:38 (page 7, lines 16-19).
The SDAB may be multivalent, bivalent, bispecific or multispecific (page 6, lines 4-6). The reference teaches that among the preferred SDABs are ALB1, ALB6, ALB7, ALB8, ALB9 and ALB10 (page 10, lines 28-33, table 3). Absent evidence to the contrary, these are the SDABs set forth in instant claims.
The reference does not teach a formulation comprising a therapeutic agent wherein the composition also comprises a therapeutic agent at a concentration from about 0.1 mg/mL to about 350 mg/mL, a lyoprotectant; and a histidine buffer at a concentration about 5 to about 50 mM, such that the pH of the formulation is about 5.0 to 7.5.
Goldstein teaches formulations for stabilization of antibodies. The formulations can be lyophilized to stabilize the antibodies during processing and storage (abstract). The antibodies disclosed include, but are not limited to, naturally occurring antibodies, bivalent fragments such as (Fab')2, monovalent fragments such as Fab, single chain antibodies, single chain Fv (scFv), single domain antibodies, multivalent single chain antibodies, diabodies, triabodies, and the like that bind specifically with antigens [paragraph 0068, emphasis added by the examiner].
The formulations comprise a histidine buffer and a lyoprotectant [paragraph 0006], which may be a sugar [paragraphs 0007 and 0008], such as sucrose [paragraph 0108]. The reference teaches that an exemplary buffer comprising the antibody concentration of about 20 mg/ml in a 10mM histidine at pH 6.0 [Example 4, paragraph 0101; these values are encompassed by the values recited in claims.
In view of the facts set forth above, it would have been prima facie obvious to a person of ordinary skill in the art at the time the invention was made to combine the prior art elements according to known methods to yield predictable results. It would have been obvious to one of ordinary skill in the art to substitute the HSA-binding SDAB taught by Beirnaert et al. for the antibody in the formulation taught by Goldstein et al. reference. One would be motivated to make such a substitution and anticipate success as Goldstein et al. teach such formulations enhance the stabilization of antibody preparations [paragraph 0004].
Claims directed to kits comprising the formulations of the instant invention. Goldstein et al teach antibody formulations in vials; the reference teaches reconstitution of formulations with 1 ml of water [paragraph 0077]. Given the broadest reasonable interpretation, a reconstituted formulation in a vial would meet the definition of a kit as recited in claimed. Goldstein et al. teach “the reconstituted formulation can be administered in a dilute form intravenously, or it can be administered in a more concentrated form by injection” [paragraph 0077]. Given these teachings, it would have been prima facie obvious to a person of ordinary skill in the art at the time the invention was made to substitute the HSA-binding SDAB taught by Beirnaert et al for the antibody in the formulation taught by the Goldstein reference and package the formulation in a prefilled injectable syringe. One would be motivated to make this modification and anticipate success because the Goldstein reference teaches administration of the reconstituted formula as an injection, and packaging said formulation as an injection would be an efficient method of delivering the therapeutic SDAB to a patient in need thereof.
Applicants argue that data in the application as filed in example 6 and the additional post-filing data in WO 2011/026948 demonstrate the unexpected result that histidine buffers are superior for molecules comprising a human serum albumin-binder. However, the claims are not commensurate in scope with the specifics of the examples for example the antibodies used are specific species while the claims are drawn to a genus. Also the examples contain additional compound during the assay which are not claimed which provide the unexpected results. The example 6 of the specification uses the specific ATN-103 which is different from the 1 amino acid conservative substitution in the CDRs sequence claimed generically. The formulation of example 6 also comprise histadine at 20 mM and not the generic claim limitation of 5-50 mM. The formulation in example 6 of the specifications have many specificity whereas the claim limitations are generic ranges in addition to different compounds such as sucrose and specific pH. The example 6 of the specification state that the stability of TNF-binding nanobody in histidine and tris buffers is essentially similar under these formulation conditions. Furthermore, the WO 2011/026948 example 1 combination of histadine, acetate, phosphate, NaCl, mannitol at different combination and pH but according to Table 2 and 6 did not result in significant stability compared to other buffers and formulations. Furthermore, RANKL in ‘948 is different from TNF nanobody of the claimed limitation and the specification does not provide nexus to the ‘948 patent for the correlation with the differences in parameters. The example 1 of ‘948 does not discuss the unexpected result of histadine buffer but rather discusses the differences in buffer. Applicants argue that example 2 of WO 2011/026948 conclusion provide unexpected results for histadine buffer. However, the IL6R304 effect does not appear much different from other buffer in Table 21. Furthermore, example 2 IL6R304 is structurally different from claimed nanobody and the nexus from the specification to the ‘948 patent regarding the methodology and how the differences in structure and formulation is not established. The example 2 of ‘948 does not discuss the unexpected result of histadine buffer but rather discusses the differences in buffer. Applicants argue that example 3 of WO 2011/026948 conclusion provide unexpected results for histadine buffer. However, Table 36 does show much difference between buffers. Furthermore, example 3 23IL60064 is structurally different from claimed nanobody and the nexus from the specification to the ‘948 patent regarding the methodology and how the differences in structure and formulation is not established. The example 3 of ‘948 does not discuss the unexpected result of histadine buffer but rather discusses the differences in buffers.
The post filing date reference upon which the unexpected results are relied upon contain additional methods and compounds which must be linked to the current specification materials and methods which leads to the nexus with the post filing date data.
Applicants argue that priority application 15/041,690 was allowed as claims as US patent 9,993,552 and the obviousness rejection was withdrawn with same evidence and arguments. It should be noted that the ‘552 patent claims are narrower in scope than the current claims. Furthermore, the issues raised above was not addressed.
Conclusion:
No claims are allowed.
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/MICHAEL D PAK/Primary Examiner, Art Unit 1674