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 . 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.
Election/Restrictions
Applicants elected group I (TGFβ binding constructs), specifically, SEQ ID 84 without traverse in the reply filed on 16 Sept, 2025. The elected species was found novel and unobvious, but non-elected species were either anticipated or found obvious in the office action of 23 Oct, 2025.
Claims Status
Claims 1, 2, 8, 10, 27, 30, 34, 37, 39, 40, 42, 47, 50, 53, 68, 69, 70, 71, 74-76, 78, 83-85, 103, 105, 106, 112, 115, 120, 127, and 129-132 are pending.
Claims 1, 2, 8, 10, 27, 30, 34, 37, 40, 42, 47, 50, 53, 56, 68, 69, 71, 74-76, 78, 106, 112, 115, 120, and 127 have been amended.
Claims 129-132 are new.
Claims 34, 39, 40, 53, 68, 69, 71, 74-76, 78, 83-85, 103, 112, 115, 120, 127, and 129-132 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 19 Sept, 2025.
Withdrawn Objections
The objection to the specification due to browser enabled code is hereby withdrawn due to amendment.
The objection to the drawings due to color is hereby withdrawn due to amendment.
Withdrawn Rejections
The rejection of claims 2, 8, 27, 37, 47, and 50 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph due to genus/subgenus issues is hereby withdrawn due to amendment.
The rejection of claim 37 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, due to inconsistencies in what is at the N-terminus is hereby withdrawn due to amendment.
The rejection of claim 8 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form is hereby withdrawn due to amendment.
The rejection of claims 10 and 37 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form is hereby withdrawn due to amendment.
The rejection of claim 42 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form is hereby withdrawn due to amendment.
Maintained/Modified Rejections
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.
first rejection
Claims 1, 2, 8, 10, 27, 30, 37, 42, 47, 50, 70, 105, and 106 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP 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. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient" (MPEP 2163).
A claimed genus may be satisfied through sufficient description of a representative number of species or disclosure of relevant, identifying characteristics such as functional characteristics coupled with a known or disclosed correlation between function and structure(MPEP 2163(3)a(II)). The number of species that describe the genus must be adequate to describe the entire genus; if there is substantial variability, a large number of species must be described.
The analysis for adequate written description considers (a) actual reduction to practice, (b) disclosure of drawings or structural chemical formulas, (c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure and (d) representative number of samples.
The issue is if a person of skill in the art would recognize a sequence comprising two TGFβ binding domains, with the specified relative inhibitory potency required by the claims.
(a and b) actual reduction to practice and disclosure of drawings or structural chemical formulas: Applicants have described a small number of different embodiments of the invention, most varying the linkers. There is a mention of using a receptor domain that binds to the target polypeptide (paragraph 136), and variants (paragraphs 139-142), but no experimental data. There is no discussion of how the linkers affect inhibitory potency.
(c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure: Applicants are claiming a polypeptide with 2 TGFβ binding sequences, where the construct has a relative inhibitory potency is greater for TGFβ1 and TGFβ3 than TGFβ2, and the inhibitory ratio of TGFβ3 to TGFβ1 is about 2.5:1 or less, with the specificity at least influenced by the linker. This is a functional limitation that the construct inhibit binding between TGFβ and its receptor, with additional functional requirements about the relative inhibitory potential between different isoforms, and that the linkers affect the relative potencies. However, applicants have provided no information of what structural features are required to meet these functional limitations. A person of skill in the art, after reading applicant’s disclosure, will not know what sequence/charge/electron density requirements are necessary to meet the functional limitations of the claims. In essence, applicants have defined their invention by function. That is not sufficient to meet the written description requirement.
Vistnes (Pharmceuticals (2024) 17:267) discusses inhibition of TGFβ (title). Direct inhibition uses antibodies or soluble TGFβ receptor domains (fig 2, 4th page, middle of page). This reference shows that, well after applicant’s priority date, agents that bound to TGFβ were limited to fragments of the natural receptors, and antibodies, suggesting no general structure/functional information is available.
Chung et al (Nat. Chem. Biol. (2009) 5(6) p407-413) discuss linker strain and flexibility in constructs with multiple binding moieties (title). Ideally, the linker would not perturb the optimal binding geometry of the binding moieties, and does not have excessive conformational flexibility due to entropic penalties (abstract). The flexibility and strain of a linker can have significant effects on binding (abstract). This reference shows that the linker can have significant effects on binding of constructs with multiple binding moieties, dependent on how the linker holds the binding moieties compared to their relative position when they are bound.
As of applicant’s priority date, it was not possible to predict if a given molecule bound to a receptor. Lowe (blog “In the pipeline” entry of 7 Sept, 2022) describes an experiment where that was attempted. 39K compounds, including known antibiotics, were screened against E. coli for growth inhibition, finding 218 active compounds (1st page, 3d paragraph). These were computer docked to a set of 296 essential bacterial proteins by multiple docking procedures (1st page, 3d paragraph), along with 100 random inactive compounds (2nd page, 1st paragraph). The number of strong binders predicted were essentially the same between the active compounds and the controls, and out of 142 compound/target interactions previously known, the methodology found only 3 (2nd page, 2nd paragraph). While a given docking program may accurately predict if compound A binds to protein B, it is impossible to a priori know if the prediction is accurate. In other words, at a date later than applicant’s priority date, it was not possible to predict if a given compound and target bound to each other.
Nor is it possible to modify known sequences to reliably find new compounds. Guo et al (PNAS (2004) 101(25) p9205-9210) looked at the effect of random mutations (title). In a DNA repair enzyme, about one mutation in three killed the activity of the protein, consistent with studies with other proteins (abstract). Yampolsky et al (Genetics (2006) 170 p1459-1472), using a different methodology, found that even conservative substitutions were prone to problems (table 3, p1465, top of page). In other words, unless there is some information known about the binding, mutating the sequence is likely to be detrimental, making it a poor way to generate new compounds.
(d) representative number of samples: Applicants have a relatively small number (about 2 dozen) of sequences, all of which appear to use the same binding sequences, and many very similar linkers. Some of these were tested for binding to TGFβ1 and TGFβ3, but not TGFβ2 (paragraph 261, table 5). There is no analysis of how the different linkers affect the relative inhibitory ratio; what structural features lead to the differences applicants have found. Nor is it clear that a person of skill in the art, using minor modifications of the test applicants used, would arrive at the same numbers (note the rejection under 35 USC 112(b) below). As there is no claim limitation combining specific binding domains with specific linkers, and it is not clear how to extrapolate from applicant’s experimental work to all TGFβ binding ligands and all linkers, the claims lack written description.
response to applicant’s arguments
Applicants argue that they have a number of examples, and that it is the length of the linker that determines the specificity.
Applicant's arguments filed 22 Jan, 2026 have been fully considered but they are not persuasive.
Applicants argue that they have a number of examples. There are two dozen very similar examples, not all of which are tested for specificity, as noted in the rejection. However, the number of linkers is essentially infinite, as there is no limitation that the amino acids used be limited to the canonical 20. Given that the prior art recognizes a number of factors beyond the length of the linker, the parameter that applicants were testing, can influence binding, this is simply not enough to fully elucidate the claimed genus. It should also be noted that there is a component of the rejection dealing with the binding to TGFβ; that has nothing to do with the linker.
second rejection
Claim 10 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP 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. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient" (MPEP 2163).
A claimed genus may be satisfied through sufficient description of a representative number of species or disclosure of relevant, identifying characteristics such as functional characteristics coupled with a known or disclosed correlation between function and structure(MPEP 2163(3)a(II)). The number of species that describe the genus must be adequate to describe the entire genus; if there is substantial variability, a large number of species must be described.
The analysis for adequate written description considers (a) actual reduction to practice, (b) disclosure of drawings or structural chemical formulas, (c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure and (d) representative number of samples.
The issue is if a person of skill in the art would understand which sequences are inherently disordered regions (IDRs) or not.
(a and b) actual reduction to practice and disclosure of drawings or structural chemical formulas: Applicants appear to be using disordered regions from the TGFβ receptor, in many instances including disordered regions adjacent to ordered binding domains. There is no discussion of what is required to generate a structure or a disordered region.
(c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure: Applicants are claiming linkers that are inherently disordered or not inherently disordered. This is interpreted as a functional requirement that the linker, under normal physiological conditions, does not fold into a defined shape, but rather remains in a random coil, or if not inherently disordered, folds into a defined shape under the same conditions. However, applicants have not described what structural features are required to meet this functional limitation. A person of skill in the art would not know what sequence/hydrogen bonding/charge requirements are necessary to meet this functional limitation. In essence, applicants have defined an important part of their invention by function. This is not sufficient to meet the written description requirement.
Howes (C&EN, issue of 1 Dec, 2020) states that, before that date, predicted structures did not match those obtained experimentally (1st page, 3d paragraph). This has been a challenge for 50 years (1st page, 1st paragraph). This reference shows that, as of applicant’s priority date, it was not possible to predict if a given sequence folded into a given structure (or not).
(d) representative number of samples: There is no demonstration that any given linker is disordered or has any particular structure in the constructs. Applicants have taken structures that are disordered in a receptor and have placed them into their constructs, and assumed that they remain disordered. But applicants have provided no evidence that this assumption holds. Nor is there any discussion of how to modify these sequences and retain the structure, or lack thereof. Given that tertiary structure was essentially unpredictable as of applicant’s priority date, the claims lack written description.
response to applicant’s arguments
Applicants argue that they have amended claim 37 to remove the language at issue, and that a person of skill in the art, with the information given in the disclosure, would know what sequences would meet the claim limitations.
Applicant's arguments filed 22 Jan, 2026 have been fully considered but they are not persuasive.
As noted in the rejection, as of applicant’s priority date, it was not possible to determine what structure a given sequence would fold into. That makes it impossible to determine if a given sequence is inherently disordered without making the sequence in the fusion protein and determining its structure.
Claim Rejections - 35 USC § 112(b)
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.
first rejection
Claims 1, 2, 8, 10, 27, 30, 37, 42, 47, 50, 70, 105, and 106 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1, and claims dependent on it, requires a structure comprising a first TGFβ binding region, a linker, a second TGFβ region, a second linker, and a multimerization domain. Dependent claims give limitations on the length of the linkers. The problem is that the cutoff between linkers and non-linker portions of the construct is arbitrary. For example, in applicant’s elected species, they appear to have stated that the structural region of a TGFβ receptor is the binding domain, and a disordered segment N-terminal to that segment in the native receptor is the linker. However, if some of the amino acids applicants have defined as the binding domain are not essential for binding, they could just as reasonably be placed into the linker. Likewise, there is nothing preventing a person of skill in the art considering the linker as part of the binding domain, as it is merely an extension of the polypeptide that formed the binding domain. This means that the length of the linker, or even if there is a linker at all, is dependent on an arbitrary determination that exists only in the mind of the person constructing the polypeptide.
response to applicant’s arguments
Applicants argue that they have limited the TGFβ binding regions to sequences comprising SEQ ID 2, and that a structured ligand-binding domain is a commonly used in the art.
Applicant's arguments filed 22 Jan, 2026 have been fully considered but they are not persuasive.
Applicants have stated that the binding region must comprise SEQ ID 2, but is not limited (“consisting of”) to that sequence; note that applicants have explicitly claimed extensions of this sequence for a longer binding region (note claim 37, for example). Nor is this limited to applicants, note Leferink et al (previously cited), p10, lines 5-11. In other words, while there are some structural limitations to the binding regions, they are not defined in such a way that there is a clear cutoff between what is and is not a binding region.
second rejection
Claims 1, 2, 8, 10, 27, 30, 37, 42, 47, 50, 70, 105, and 106 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1, and claims dependent on it, requires that the relative inhibitory potency of the construct against TGFβ1 and TGFβ3, as measured by IC50, be less than 2.5. The issue is the use of IC50 as the measurement of potency. As discussed by the Canadian society of pharmacology dictionary definition of the Cheng-Prussoff equation (https://pharmacologycanada.org/Cheng-Prusoff-equation, downloaded 20 Dec, 2025), IC50 is the concentration at which a compound displaces half of a ligand (2nd page, 1st paragraph). This is related to the absolute binding affinity (Ki) by an equation that requires the concentration of the ligand and its affinity to the receptor (2nd page, 1st paragraph). In other words, the IC50 is dependent on the measurement conditions used in the assay, which are not defined by the claims. If an embodiment meets the inhibitory potency requirement under one set of conditions, but not another, it is not clear if the claim limitations have been met. Note that the test used by applicants is a subtractive test, where a mixture of TGFβ and the inhibitor to be tested are placed on cells, and the activity of the TGFβ measured (example 2). This test is dependent on the concentration of TGFβ, and does not measure IC50.
response to applicant’s arguments
Applicants argue that amending the claims to require a A549/IL-11 cell based assay overcomes the rejection.
Applicant's arguments filed 22 Jan, 2026 have been fully considered but they are not persuasive.
The issue with the claims described by the rejection is that the IC50 measurement is variable, and dependent on parameters not described, such as the concentration of the displaced compound and its affinity. Specifying that the assay use a specific cell line and a specific cytokine does not change the basis of the problem.
third rejection
Claim 10 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 10 and 37 allow for hybrid linker variants, truncated likers, elongated linkers, and variants. A hybrid linker is defined as an IDR linker with a glycine and serine substituted in (paragraph 123), and a hybrid variant linker is a hybrid linker with substitutions. It is not clear what the cutoff is between an IDR linker and a hybrid variant linker. A truncated linker is an IDR linker that has had one or more amino acids truncated from either or both ends (paragraph 126). It is not clear what the difference is between a truncated linker and an IDR linker. Similarly, an elongated linker is a linker with additional residues added (paragraph 133). However, this is still a linker, making it unclear what differentiates an elongated linker from a non-elongated linker. In essence, applicants have defined these linkers in relationship to another linker, which is not defined.
response to applicant’s arguments
Applicants state that they have removed the problematic language from claim 37, and that a person of skill in the art, armed with the disclosure, would know what these terms mean.
Applicant's arguments filed 22 Jan, 2026 have been fully considered but they are not persuasive.
That a person of skill in the art would understand what the terms mean is not the issue. The problem is applying these definitions to a given linker.
Claim Rejections - 35 USC § 102
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.
Claim(s) 1, 2, 8, 10, 27, 30, 37, 42, 47, 50, 70, 105, and 106 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Lenferink et al (WO 2018158727, cited by applicants).
Please note that this application was published less than 1 year prior to applicant’s priority date. Because of this, applicants may be able to apply one or more exceptions under 35 USC 102(b)(1) and/or (b)(2).
Lenferink et al discuss a polypeptide construct, where a first and second TGFβ binding domain are attached to an antibody heavy chain attached to the C-terminus (p2, 5th paragraph). The antibody heavy chain is a dimerization domain (p3, 2nd paragraph). This can contain two constant domains (p3, 3d paragraph), which is interpreted as a linker and a multimerization domain. Binding domains identical to those of applicant’s elected species, with flexible flanking sequences, are mentioned (p9, 1st and 2nd paragraphs), which are disclosed as binding to TGFβ1 and TGFβ3 stronger than TGFβ2 (p9, 3d paragraph). These two domains can be connected by a linker (p9, 5th paragraph), including intrinsically disordered linkers (p10, 2nd and 3d paragraphs). Note that these sequences comprise SEQ ID 8 of the examined claims. Alternatively, the linker can be a repeating GGGGS moiety, with 0-50 repeats (p10, 2nd paragraph). A construct described as TGFβ binding domain-linker- TGFβ binding domain-linker-CH2-CH3 is mentioned (p11, 2nd paragraph). These antibody constant regions dimerize via disulfide bond formation (p11, 3d paragraph). When secreted from a production host, these constructs will dimerize (p14, 2nd paragraph), presumably as homodimers. Pharmaceutically acceptable diluent, excipient, and carriers are discussed (p18, 5th paragraph).
The reference discusses sequences that have a TGFβ binding domain, a linker a second TGFβ binding domain, a second linker, and a multimerization domain, where the affinity to TGFβ1 and TGFβ3 is greater than for TGFβ2. The length of the linker is arbitrary, depending on where the person designing it describes the linker. Alternatively, a linker explicitly meeting the length requirements was discussed. This construct has every structural feature that applicants have stated is required for similar TGFβ1 and TGFβ3 activity, so that is inherent. Alternatively, an appropriate ligand and concentration can be selected so that the two IC50 readings will be similar. Thus, the reference anticipates claims 1, 2, and 8.
The linkers are described as disordered, anticipating claim 10.
The linkers comprise SEQ ID 8 of the examined claims, anticipating claims 27 and 30.
The construct comprises the same sequence used by applicants, with the same disordered region, anticipating claim 37.
The construct comprises the CH2 and CH3 domain of an antibody, anticipating claims 42 and 47.
The construct forms a disulfide bond in the multimerization domain, anticipating claims 50 and 70.
The construct presumably forms homodimers, anticipating claim 105.
Formulations with suitable carriers, diluents, and excipients are discussed, anticipating claim 106.
response to applicant’s arguments
Applicants argue that the linkers are longer than the claims allow.
Applicant's arguments filed 22 Jan, 2026 have been fully considered but they are not persuasive.
Applicant’s arguments assume that the binding domain consists of SEQ ID 2. However, it clearly can be longer, note claim 37. In addition, the rejection has been modified to allow for alternative linkers.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 2, 8, 10, 27, 30, 37, 42, 47, 50, 70, 105, and 106 are rejected under 35 U.S.C. 103 as being unpatentable over Zwaagstra et al (WO 2017037634) in view of Huang (Curr. Opinion. Biol. (2009) 20 p692-699).
Zwaagstra et al discuss at least two TGFβ binding domains linked to the C-terminus of an antibody constant domain (p2, 5th paragraph). The antibody domain can have CH2 and CH3 domains, which dimerize by cross linking cysteines (p5, 6th paragraph), i.e. multimerization domain. The same TGFβ binding domains used in applicant’s examples are discussed, in the same order (p19, 4th paragraph). Note that this has a spacer between the two domains (compare the sequence with those of p19, 2nd paragraph). Note that many of the spacers described by the reference are between 10 and 33 amino acids long. The antibody constant domain can be linked to the binding domains by a linker (p22, 6th paragraph, continues to p23). These can be coupled by intrinsically disordered regions, such as various SEQ IDs that comprise SEQ ID 8 of the examined application (p23, 2nd and 3d paragraphs). Likewise, the receptor binding domains can be linked by similar linkers (p23, 4th paragraph). When secreted into the cell culture medium where they are grown, the constructs dimerize into homodimers (p24, 4th paragraph). These can be mixed up with a pharmaceutically acceptable carrier, diluent, or excipient (p8, 3d paragraph).
The difference between this reference and the examined claims is that this reference places the antibody fragment on the N-terminus of the construct, rather than the C-terminus.
Huang discusses Fc fusion traps (title). These form dimers, including homodimers, which can increase affinity due to avidity (p693, 1st column, 2nd paragraph). An example is given of a trap molecule, comprising two IL-1 binding domains, attached at the C-terminus to an antibody Fc domain (p695, 2nd column, 2nd paragraph), along with an example discussing VEGF binding domains attached at the C-terminus to an antibody Fc domain (p695, 2nd column, 3d paragraph). This reference discusses antibody Fc domains attached to the C-terminus of a trap molecule.
Therefore, it would be obvious to attach the antibody fragment to the C-terminus of the construct of Zwaagstra et al, instead of the N-terminus, as a simple substitution of one known element for another yielding expected results, as discussed by Huang. As Huang discuss the same features discussed by Zwaagstra et al (increased avidity), an artisan in this field would attempt this modification with a reasonable expectation of success.
Zwaagstra et al discuss the same binding agents as applicants, which will necessarily have the same activities, linked via disordered regions, attached to an antibody Fc multimerization domain at the N-terminus via a linker. Many of the linkers listed by Zwaagstra et al are between 10 and 33 amino acids long. Huang renders obvious moving the antibody domain (and linker) to the C-terminus, rendering obvious claims 1, 2, 8, and 10.
The linkers comprise SEQ ID 8 of the examined claims, rendering obvious claims 27 and 30.
The binding sequence of Zwaagstra et al is the same as that of applicants, so it contains the same N-terminal disordered region, rendering obvious claim 37.
The multimerization domain forms a cysteine dimerization, rendering obvious claims 42, 50, and 70.
The multimerization domain is an antibody Fc domain, rendering obvious claim 47.
The reference mentions homodimers, rendering obvious claim 105.
The reference mentions pharmaceutically acceptable diluents, excipients, and carriers, rendering obvious claim 106.
response to applicant’s arguments
Applicants argue that the rejection does not meet the limitation that the linkers be between 10 and 33/34 amino acids in length and claim unexpected results that the claimed material has better selectivity.
Applicant's arguments filed 22 Jan, 2026 have been fully considered but they are not persuasive.
There are two issues with the argument regarding the spacer. First, as noted in the rejection as amended, the reference explicitly describes linkers that meet the length limitations of the claims. Second, as noted in the rejection under 35 USC 112(b), above, the cutoff between the linker and the binding regions are arbitrary.
Applicants claim of unexpected results is also not persuasive. First, unexpected results must be commensurate in scope with the claimed invention (MPEP 716.02(d)). As noted in various rejections under 35 USC 112(a) and (b), this is not the case. Second, unexpected results are compared to the closest prior art, in this case, Zwaagstra et al. As noted in the rejection as amended, this reference discusses linkers that match the size described by applicants, which applicants state is the determining factor.
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.
Claims 1, 2, 8, 10, 27, 30, 37, 42, 47, 50, 70, and 105 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 14 of U.S. Patent No. 12,391,743 in view of Huang (Curr. Opinion. Biol. (2009) 20 p692-699).
Comepeting claim 1 describes an antibody CH2 and/or CH3 domain attached to a segment containing at least two TGFβ binding domains. Competing claim 14 describes SEQ ID 46, which describes the same binding domains as the examined claims, connected with a linker comprising SEQ ID 8 of the examined claims.
The difference between the competing claims and the examined claims is that the competing claims place the antibody domain on the N-terminus, rather than the C-terminus.
Huang discusses Fc fusion traps (title). These form dimers, including homodimers, which can increase affinity due to avidity (p693, 1st column, 2nd paragraph). An example is given of a trap molecule, comprising two IL-1 binding domains, attached at the C-terminus to an antibody Fc domain (p695, 2nd column, 2nd paragraph), along with an example discussing VEGF binding domains attached at the C-terminus to an antibody Fc domain (p695, 2nd column, 3d paragraph). This reference discusses antibody Fc domains attached to the C-terminus of a trap molecule.
Therefore, it would be obvious to attach the antibody fragment to the C-terminus of the construct of the competing claims, instead of the N-terminus, as a simple substitution of one known element for another yielding expected results, as discussed by Huang. As Huang discusses other trap molecules with the antibody fragment at the C-terminus, an artisan in this field would attempt this modification with a reasonable expectation of success.
response to applicant’s arguments
Applicants request that this rejection be held in abeyance until the application is otherwise found to be in condition for allowance. However, until the rejection is overcome, it will remain valid.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRED REYNOLDS whose telephone number is (571)270-7214. The examiner can normally be reached M-Th 9-3:30.
Examiner interviews are available via telephone 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, Melissa Fisher can be reached at 571-270-7430. 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.
/FRED H REYNOLDS/Primary Examiner, Art Unit 1658