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 .
Requirement for Information
Applicant and the assignee of this application are required under 37 CFR 1.105 to provide the following information that the examiner has determined is reasonably necessary to the examination of this application.
In response to this requirement, please provide answers to each of the following interrogatories eliciting factual information:
What is the amino acid sequence of the ankyrin repeat domain with binding specificity to the epsilon component of the CD3 complex disclosed in the following reference:
“Application of the DARPin ®technology for specific targeting of tumor-associated MHC class I:peptide complexes” published in part by inventor Victor Levitsky and assignee Molecular Partners in Cancer Research, (August 2020) Vol. 80, No. 16 SUPPL. Abstract Number: 690 and at the American Association for Cancer Research Annual Meeting, AACR 2020. Philadelphia, PA, United States. 22 Jun 2020-24 Jun 2020.
The applicant is reminded that the reply to this requirement must be made with candor and good faith under 37 CFR 1.56. Where the applicant does not have or cannot readily obtain an item of required information, a statement that the item is unknown or cannot be readily obtained may be accepted as a complete reply to the requirement for that item.
This requirement is an attachment of the enclosed Office action. A complete reply to the enclosed Office action must include a complete reply to this requirement. The time period for reply to this requirement coincides with the time period for reply to the enclosed Office action.
Election/Restrictions
The requirement for restriction and election mailed February 18, 2026, is withdrawn.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application Nos. PCT/EP2021/086331, 63182394, 63126356, and EP20216705.2 fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The reason is the same as that presented in the written description and enablement rejections below.
The earliest effective filing date of claims 1-20 is the filing date of the instant application June 15, 2023.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-20 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 states that the written description requirement for a claimed genus may be
satisfied through sufficient description of a representative number of species by actual reduction
to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other
physical and/or chemical properties, by functional characteristics coupled with a known or
disclosed correlation between function and structure, or by a combination of such identifying
characteristics, sufficient to show the applicant was in possession of the claimed genus.
Scope of the claims
The claims are drawn to recombinant binding proteins comprising an ankyrin
repeat domain with binding specificity for cluster of differentiation 3 (CD3). Claims 1-7 and 9-14 are drawn to ankyrin repeat domains comprising an ankyrin repeat module having an amino acid sequence selected from SEQ ID NOs: 5-9 and sequences in which up to 9 amino acids in any of SEQ ID NOs: 5-9 are substituted. Claims 8 and 15-20 are drawn to ankyrin repeat domains with at least 80% identity to SEQ ID NO: 1-4.
The specification defines the claim term "ankyrin repeat domain" as a repeat domain
comprising two or more consecutive ankyrin repeat units (modules) as structural units, and,
preferably, an N-terminal and/or a C-terminal capping unit (or module) (p. 45). This modular architecture yields an elongated protein domain with a structural scaffold, continuous hydrophobic core, and an elongated surface available for optimization and binding to target ligands. The term "ankyrin repeat module" is defined as a repeat module derived from the repeat units of naturally occurring ankyrin repeat proteins (p. 46). Each module is 33 amino acids in length and contains a b-turn, two antiparallel a-helices and a loop. Figure 1 from Binz (NPL 2, IDS 6/15/2023) illustrates the general structure of these molecules. An ankyrin repeat domain is assembled from an N-terminal capping ankyrin repeat module (green), two or three designed ankyrin repeat modules (blue) and a C-terminal capping ankyrin repeat module (cyan) (Figure 1b):
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to yield (Figure 1c):
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The libraries utilized to identify ankyrin repeat domains that bind to CD3 in the
instant application are related to those disclosed by Binz (NPL 2, IDS 6/15/2023). The
theoretical diversities of the libraries of Binz are 5.2x10¹⁵ (N2C) and 3.8x10²³ (N3C), and the
actual diversity of the libraries are 10¹⁰ individual members each (Binz, p. 577, col 2). The
diversity of these libraries, which involve variation at 6 of the 33 positions in the repeat and
shuffling of different N-cap, designed modules and C-cap modules, illustrate the structural
complexity of the instant genus and the enormous number of sequences that meet the structural
definition of ankyrin repeat domain. In addition, variation at up to nine positions in an ankyrin repeat module yields 209 different modules.
However, only those sequences meeting both the structural and functional requirements
of the genus are encompassed by the claim; the claimed genus is limited to those sequences that
qualify structurally as ankyrin repeat domains that are also able to bind CD3. Thus, to satisfy the written description requirement the specification must provide sufficient information to distinguish ankyrin repeat domain sequences that bind to CD3 with specificity from those that do not bind to CD3.
Actual Reduction to Practice
MPEP § 2163 states that the written description requirement for a claimed genus may be
satisfied through sufficient description of a representative number of species by actual reduction
to practice A "representative number of species" means that the species which are adequately
described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the
genus.
In the instant case, several embodiments of the invention were reduced to practice:
ankyrin repeat modules 5-9, and ankyrin repeat domains SEQ ID NOs: 1-4.
The general structure of these embodiments is as follows:
Ankyrin repeat domain SEQ ID NO: 1
[N-terminal cap]-[SEQ ID NO: 5 module]-[SEQ ID NO: 6 module]-[C-terminal cap]
SEQ ID NO: 2
[N-terminal cap]-[SEQ ID NO: 7 module]-[SEQ ID NO: 6 module]-[C-terminal cap]
SEQ ID NO: 3
[N-terminal cap]-[SEQ ID NO: 7 module]-[SEQ ID NO: 8 module]-[C-terminal cap]
SEQ ID NO: 4
[N-terminal cap]-[SEQ ID NO: 7 module]-[SEQ ID NO: 8* module]-[C-terminal cap]
*SEQ ID NO: 8 with two substitutions
The structural genus of ankyrin repeat domains is enormous and diverse (see discussion above). The claimed genus is a subset of ankyrin repeat domains which are defined, not only by the well-characterized structural features of the ankyrin scaffold, but by the particular function of CD3 binding as well. The scope of the CD3 binding subgenus is not structural defined, in either the specification or the prior art. On the contrary, empirical selection of species from a random collection of ankyrin repeats followed by affinity maturation and design is utilized to identify members of the genus. Therefore, one of ordinary skill in the art would not consider ankyrin repeat modules SEQ ID NOs: 5-9, and ankyrin repeat domains SEQ ID NOs: 1-4 to be representative of the full scope of the claimed genus. The instant specification has failed to meet the written description requirement by actual reduction to practice of a representative number of species alone.
Sufficient relevant identifying characteristic
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction
to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination thereof.
i. Complete structure
As stated above, the complete structure of ankyrin repeat modules SEQ ID NOs: 5-9, and ankyrin repeat domains SEQ ID NOs: 1-4 are disclosed. The amino acid sequences of these species are insufficient to suggest how the selected design ankyrin repeat domains (DARPins) bind to CD3. The specification does not present the structure of one of these species bound to CD3. The Examiner is not aware of a structure of an ankyrin repeat protein bound to CD3 that could be used to suggest an epitope or binding mechanism. Likewise, the Examiner is not aware of an ankyrin repeat in nature that binds to CD3 and a correspond structure-activity analysis.
ii. Partial structure
The specification asserts that proteins having at least 80% identity to SEQ ID NOs:1-4 are within the scope of the claims. In addition, the specification asserts that ankyrin repeat modules having an amino acid sequence selected from the group consisting of SEQ ID NO: 5-9 and sequences, wherein up to 9 amino acids in SEQ ID NO:5-9 are exchanged by any amino acid are also within the scope of the claims.
This level of structural description is insufficient to define the instantly claimed genus which requires binding to CD3 not merely the adoption of an ankyrin repeat canonical fold. The DARPin libraries disclosed by Binz and related to those used in the instant application to select for sequences that bind CD3 utilize repeats with 27 fixed positions and six randomized positions. Therefore, a large portion of the DARPin library meets the requirement of having ankyrin modules that differ from SEQ ID NOs: 5-9 in up to 9 positions. Sequences meeting this minimal structural requirement are known to bind with high-affinity to a diverse array of targets. For example, Binz discloses ankyrin repeat domains that bind maltose binding protein (MBP) and two eukaryotic kinases with affinities in the low nanomolar range (p. 576, col 2, p. 577, col 1).
Furthermore, each of US 7,417,130, US 2011/0207668, US 8,110,653, US 2012/0142611, US 2012/0277143, US 2013/0116197, US 2013/0244940, US 2013/0296221, US 8,710,187, US 2009/0082274, US 2014/0221295, and US 8,722,618 disclose design ankyrin repeats that are structurally similar to the instant sequences but which bind to targets other than CD3. Therefore, the minimal structural information presented in the specification is insufficient to define the claimed subgenus of ankyrin repeat domains that bind CD3.
The specification states that the ankyrin repeat domains that bind CD3 comprise a repeat module with the ankyrin repeat sequence SEQ ID NOs: 5-9 and sequences wherein up to 9 amino acids in any of SEQ ID NOs: 5-9 are exchanged by any amino acid. Although this definition may appear narrow, it includes 920 possible sequences. The specification does not make it clear that all of these sequences could be expected to bind to CD3. Therefore, this formula does not constitute a partial structure of the claimed genus.
iii. Physical and/or chemical properties
The data presented in the specification raise more questions about the physical properties
of the genus than they answer. The data do not suggest the physical basis for the CD3 binding activity and therefore do not describe which substitutions, deletions or additions could be made while preserving function. The specification does not describe which residues form the binding site, influence the binding site formation indirectly, contact the binding site in the folded protein, or have a role in the overall stability and dynamics of the folded protein. Understanding the physical basis for CD3 binding is critical to determining which of the sequences that meet the structural requirements of the genus also meet the functional requirements of the genus.
iv. Functional characteristics when coupled with a known or disclosed
correlation between function and structure
The specification does not describe a general correlation between structure and function
for the claimed genus. The role of the specific amino acids of the select ankyrin repeat domains
in the binding site, binding site formation, binding site environment and overall fold, stability
and dynamics of the protein are not described. As a result, it is impossible to predict, based on
the specification, how changing any position will affect binding to CD3.
As stated previously, the specification does not present the structure of one SEQ ID NOs:
1-4 bound to CD3. The Examiner is not aware of a structure of an ankyrin repeat protein
bound to CD3 that could be used to suggest an epitope or binding mechanism. Likewise, the Examiner is not aware of an ankyrin repeat in nature that binds to CD3 and a correspond structure-activity analysis. Absent this information from the prior art, the specification must provide the structure-function correlation and in this case fails to do so.
v. Method of Making
The specification discloses an empirical method for identifying ankyrin repeat domains
that bind to CD3. Ribosomal display technology is used to screen for ligands followed by affinity maturation and design. An empirical means to screen for members of a genus does not constitute
possession of the genus, which is the requirement of written description. Without empirical determination, it is not possible for one of ordinary skill in the art to distinguish based on sequence alone which ankyrin repeat domains will bind to CD3.
Conclusion
Each of the factors have been considered with respect to the scope of the genus
throughout the analysis above. There is a large body of work in the designed ankyrin repeat art
and yet there is a high level of unpredictability and complexity associated with identifying the specific sequences of ankyrin repeats that bind to CD3. The prior art does not present clear rules to distinguish ankyrin repeat domains that can bind CD3 from those that are not capable of this interaction. For these reasons, the skilled artisan would not reasonably conclude that the inventor(s), at the time the application was filed, had possession of the full scope of the claimed invention. Only SEQ ID NOs: 1-4 satisfy the written description requirement.
Claims 14-15 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
To comply with the enablement requirements of 35 U.S.C. §112, first paragraph, a specification must adequately teach how to make and how to use a claimed invention throughout its scope, without undue experimentation. Plant Genetic Systems N.V. v. DeKalb Genetics Corp., 315 F.3d 1335, 1339, 65 USPQ2d 1452, 1455 (Fed. Cir. 2003). There are a variety of factors which may be considered in determining whether a disclosure would require undue experimentation. These factors include: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The Nature of the Invention
The invention is in the technical field of designed ankyrin repeat domain proteins with binding specificity for CD3 and their use in treating medical conditions.
The breadth of the claims
The claims are drawn to ankyrin repeat domains with at least 80% identity to SEQ ID NO: 1-4. Although this limitation may appear to be narrow, up to 20% variation in a 124 amino acid residues sequence yields a countless number of species that meet the structural requirements of the claims. The genus is functionally limited to species with binding specificity to CD3.
The scope of the claims with respect to patient population includes patients suffering from or at risk of developing medical conditions that can be treated by targeting CD3, including cancers and infectious diseases (specification, pp. 42-44) and autoimmune disorders, inflammatory disorders, retinopathies, neurodegenerative disorders, and metabolic diseases (specification, pp. 49-50).
The State of the Prior Art
The Examiner is not aware of prior art disclosing the use of the claimed compositions to treat any medical condition.
The Predictability or Unpredictability of the Art
The level of unpredictability with respect to the ankyrin repeat domains is discussed in the written description rejection above and is incorporated here. In addition, the level of unpredictability in the art with respect to treatment of cancers, infectious diseases, autoimmune disorders, inflammatory disorders, retinopathies, neurodegenerative disorders, and metabolic diseases is high.
The Presence or Absence of Working Examples
The specification discloses the working examples relevant to claims 14-15. See especially Examples 5-9. In these examples, the ankyrin repeat domains SEQ ID NOs: 1-4 (i.e. DARPin® 1-4) are incorporated into trispecific or tetraspecific T-cell engager (TCE) molecules. A TCE comprises an ankyrin repeat domain that binds CD3 as well as ankyrin repeat domains that bind a disease-associated antigen. The ankyrin repeat domains SEQ ID NOs: 1-4 were combined with ankyrin repeat domains that bind two different tumor-associated antigens, TAA2 (CD123) and TAA3 (CD33), for the trispecific format (DARPin® protein #A, #B, #C and #D, respectively) or the same with an ankyrin repeat domain that binds human serum albumin for the tetraspecific format. The ankyrin repeat domains were connected to each other by a peptide linker, such as the linker of SEQ ID NO: 31. See Example 5.
Example 5 assesses binding to primary T cells isolated from human peripheral blood mononuclear cells (PBMCs). The proteins show a broad range of affinities from no binding detectable for #A to binding as good as benchmark molecules for #D (Figures 8A-B), consistent with CD3 affinity measured by SPR. The presence of an additional HSA binding domain (see Figure 8B) had only a minor impact on binding to T cells.
Example 6 assesses target-specific short-term tumor cell killing by LDH cytotoxicity assay. For DARPin® proteins without half-life extension, DARPin® protein #B and DARPin® protein #C induced tumor cell killing comparable to benchmark molecule, whereas DARPin® protein #A and DARPin® protein #D show 10 to 100-fold lower potency (Figure 9A). For DARPin® proteins with half-life extension, DARPin® proteins show about 4 to 70-fold reduction in potency compared to the corresponding non-half-life extended molecules (Figure 9B).
Example 7 assesses target-specific short-term T cell activation and INFg secretion. DARPin® protein #B and DARPin® protein #C, without half-life extension, induced specific short-term T-cell activation comparable to benchmark molecules, whereas DARPin® protein #A and DARPin® protein #D showed 10 to 100-fold lower potency (Figure 10A). Half-life extended DARPin® proteins showed about 3- to 100-fold reduction in potency compared to the corresponding non-half-life extended molecules (Figure 10B).
Example 8 assesses target-specific long-term tumor cell killing. DARPin® proteins #B, #C and #D show potent and specific tumor cell killing, comparable to benchmark molecules, independent of half-life extension. Only the lower-affinity DARPin® #A shows a reduction of killing potency. See Figure 12.
Example 9 assesses target-specific long-term T cell activation and proliferation by FACS. DARPin® proteins #B and #C, without half-life extension, induced long- term T-cell activation and proliferation comparable to benchmark molecules, whereas DARPin® proteins #A and #D show 10 to 100-fold lower potency (Figures 13 and 14). Half-life extended CD3-specific ankyrin repeat proteins show about 5- to 30-fold reduction in potency compared to the corresponding non-half-life extended molecules.
Example 10 evaluates in vivo efficacy for multi-specific TCE binding proteins in PBMC humanized mice and TAA-expressing tumor models.
In Experiment A, DARPin® protein #2, DARPin® protein #3 and DARPin® protein #4 were formatted into tetra-specific TCE molecules, which in addition to the CD3 binding ankyrin repeat domains comprise ankyrin repeat domains with binding specificity for TAA2, TAA3, and human serum albumin, each linked by SEQ ID NO: 31 (DARPin® protein #F, #G, and #H, respectively). DARPin® protein #2 was similarly formatted into a tri-specific TCE molecule, which in addition to the CD3 binding ankyrin repeat domain comprises the ankyrin repeat domains with binding specificity for TAA2 and TAA3, but lacks the HSA-specific ankyrin repeat domain (DARPin® protein #E). All proteins were tested in a Peripheral Blood Mononuclear Cell (PBMC) humanized mouse model bearing a TAA2/TAA3-expressing tumor cell line as solid subcutaneous tumor and compared to a known TAA3 targeted T cell engager molecule currently tested in clinical trials. All multi-specific binding proteins tested show antitumoral activity and the half-life extended molecules, have stronger antitumoral activity than the not half-life extended molecule. See Figure 15.
In Experiment B, DARPin® protein #3 was formatted into a hexa-specific TCE molecule, which additionally comprises three designed ankyrin repeat domains with binding specificity for TAA2, TAA3 and TAA4, respectively, and two designed ankyrin repeat domains with binding specificity for human serum albumin. This protein was tested in a Peripheral Blood Mononuclear Cell (PBMC) humanized mouse model bearing a TAA2/TAA3/TAA4-expressing tumor cell line (Molm-13) as solid subcutaneous tumor and compared to a known TAA3 targeted T cell engager molecule currently tested in clinical trials. This protein showed good efficacy in terms of inhibition of tumor growth and tumor volume over the entire time of the experiment (Figure 16A) and at 17 days after the first injection (Figure 16B). This result further demonstrated that the CD3-specific ankyrin repeat domains of the invention can be combined with TAA-specific binding domain(s) and half-life extending moietie(s) to form T cell engager molecules with anti-tumor activity in vivo. Thus, when formatted in such TCE molecules, the CD3-specific ankyrin repeat domains of the invention maintain their ability to bind to CD3 and activate T cells in vivo.
The Level of Guidance in the Specification
The specification does not provide any working examples that are specific to infectious diseases, autoimmune disorders, inflammatory disorders, retinopathies, neurodegenerative disorders, or metabolic diseases (specification, pp. 49-50).
Examples 5-10 are relevant to the medical condition cancer. However, the specification fails to provide necessary guidance to enable one of ordinary skill in the art to identify which cancers can be treated. The CD3-binding ankyrin repeat domains SEQ ID NOs: 1-4 are combined with ankyrin repeat domains that bind two different tumor-associated antigens, CD123 and CD33. The specification does not identify tumor type. As a result, one of ordinary skill in the art does not know which tumor type is treated in the examples or if other tumor types can be treated. In addition, it is not clear if the CD3-binding ankyrin domains work with domains that bind other tumor-associated antigens. In addition, it is not clear if the CD3-binding ankyrin domains work on their own or if they are only effective to treat a condition if combined with other ankyrin domains in a TCE format.
The Quantity of Experimentation Necessary
Considering the factors above, the skilled artisan would be burdened with undue experimentation in determining if one of the claimed ankyrin repeat proteins would be effective at treating a medical condition. The skilled artisan would be burdened with testing a broad range of ankyrin repeat proteins in in vitro assays. The active molecules would then have to be subjected to animal models relevant to the individual diseases to be treated. The experimentation required represents years of inventive effort. When the above factors are weighed, it is the examiner's position that one skilled in the art could not practice the invention without undue experimentation.
Therefore, in view of the Wands factors, the claims appear to require undue experimentation to use the full scope of the claimed invention.
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.
Claims 1-20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Reschke et al. (US 2023/0056271 A1, published February 23, 2023).
Reschke et al. teach a recombinant binding protein comprising an ankyrin repeat domain with binding specificity for CD3, wherein said ankyrin repeat domain comprises an amino acid sequence that is at least 85% identical to anyone of the amino acid sequences of SEQ ID NOs: 1 to 5 (SEQ ID NOs: 1-4 are identical to instant SEQ ID NOs: 1-4, respectively) ([0025]). This satisfies all of the limitations of instant claims 1-8.
Regarding claims 9 and 16, Reschke et al. teach that the protein binds human CD3 in PBS with a dissociation constant (KD) below 10−6 M ([0041]).
Regarding claims 10 and 17, Reschke et al. teach that the protein binds human CD3 in PBS with an EC50 ranging from 1 to 400 nM ([0041]).
Regarding claims 11 and 18, Reschke et al. teach that the binding protein further comprises a second binding agent that specifically binds to a first tumor-associated antigen (TAA1), a third binding agent that specifically binds to a second tumor-associated antigen (TAA2), and a fourth binding agent that specifically binds to a third tumor-associated antigen (TAA3) ([0026]).
Regarding claims 12 and 19, Reschke et al. teach that the protein further comprises a half-life extending moiety, preferably wherein said half-life extending moiety is a binding agent that specifically binds to human serum albumin ([0046]).
Regarding claims 13 and 20, Reschke et al. teach a nucleic acid encoding such a recombinant protein ([0050]).
Regarding claim 14, Reschke et al. teach a pharmaceutical composition comprising such a recombinant protein or the nucleic acid encoding such a recombinant protein, and a pharmaceutically acceptable carrier and/or diluent ([0051]).
Regarding claim 15 , Reschke et al. teach a method of treating a medical condition, the method comprising the step of administering to a patient in need thereof a therapeutically effective amount of such a recombinant protein, or of a pharmaceutical composition comprising said recombinant protein ([0052]).
Claim Rejections - 35 USC § 102/103
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.
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.
Claims 1, 9-10, and 13 are rejected under pre-AIA 35 U.S.C. 102(b) as anticipated by or, in the alternative, under pre-AIA 35 U.S.C. 103(a) as obvious over Binz (NPL 2, IDS 6/15/23).
Binz teaches a library of designed ankyrin repeat proteins. Each protein in the library comprises an ankyrin repeat domain assembled from an N-terminal capping ankyrin repeat module (green), two or three designed ankyrin repeat modules (blue) and a C-terminal capping ankyrin repeat module (cyan) (Figure 1b):
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to yield (Figure 1c):
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Sequences of the N-terminal capping module, the designed ankyrin repeat module and the C-terminal capping module with secondary structure elements indicated above the sequences are shown in Figure 1a:
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The designed ankyrin module consists of 26 defined framework residues, six randomized potential interaction residues (red x, any of the 20 natural amino acids except cysteine, glycine or proline) and one randomized framework residue (z, any of the amino acids asparagine, histidine or tyrosine).
The ankyrin repeat proteins taught by Binz comprise an ankyrin repeat module having an amino acid sequence consisting of the ankyrin repeat module instant SEQ ID NOs: 5-6 and 9, wherein up to 9 amino acids are exchanged by another amino acid, satisfying the structural limitations of claim 1:
Binz xDxxGxTPLHLAAxxGHLEIVEVLLKzGADVNA
SEQ ID NO: 5 KDSQGWTPLHTAAQTGHLEIFEVLLKAGADVNA 9 differences
SEQ ID NO: 6 KDDKGVTPLHLAAALGHLEIVEVLLKAGADVNA 7 differences
SEQ ID NO: 7 KNSRGWTPLHTAAQTGHLEIFEVLLKAGADVNA 10 differences
SEQ ID NO: 8 KNDKRVTPLHLAAALGHLEIVEVLLKAGADVNA 9 differences
With respect to claim 13, Binz teaches nucleic acid encoding the ankyrin repeat
domains (Figure 1; pp. 580-581).
Binz is silent with respect to the claimed functional features of the instant ankyrin
repeat domains and modules. Binz does not explicitly teach binding to CD3.
MPEP §§ 2112- 2112.02 states that a rejection under 35 U.S.C. 102/103 is proper when
the reference discloses all the limitations of a claim except a property or function, and the
examiner cannot determine whether or not the reference inherently possesses properties which
anticipate or render obvious the claimed invention but has basis for shifting the burden of proof
to applicant as in In re Fitzgerald, 619 F.2d 67, 205 USPQ 594 (CCPA 1980).
In the instant case, the ankyrin repeat library meets all of the structural requirements of the instant claims. However, Binz is silent as to whether any members of the library are capable of binding to CD3. Because the prior art proteins are structurally identical to those claimed, there is sufficient basis for shifting the burden of proof to Applicant. See In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). The prima facie case can be rebutted by evidence showing that the prior art products do not necessarily possess the characteristics of the claimed product. In re Best, 562 F.2d at 1255, 195 USPQ at 433. See also Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985) and MPEP §§ 2112- 2112.02.
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 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 11,834,504. Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims anticipate the instant claims.
Patented claim 1 recites a recombinant protein comprising (1) a first binding agent that specifically binds to a protein expressed on the surface of an immune cell, and (2) at least two binding agents that specifically bind to a tumor-associated antigen, wherein said two binding agents specifically bind to different tumor-associated antigens, and wherein said first binding agent is a designed ankyrin repeat domain with binding specificity for CD3, and wherein said ankyrin repeat domain with binding specificity for CD3 comprises an amino acid sequence that is at least 85% identical to any one of the amino acid sequences of SEQ ID NOs: 1 to 5. Patented SEQ ID NOs: 1-4 are identical to instant SEQ ID NOs: 1-4, respectively. This satisfies all of the limitations of instant claims 1-8, 11, and 18.
Regarding claims 9 and 16, patented claim 7 requires that the protein binds human CD3 in PBS with a dissociation constant (KD) below 10−6 M.
Regarding claims 10 and 17, patented claim 8 requires that the protein binds human CD3 in PBS with an EC50 ranging from 1 to 400 nM.
Regarding claims 12 and 19, as evidenced by Table 19, several of the claimed species comprise a half-life extension domain that binds HSA.
Regarding claims 13 and 20, patented claim 19 requires a nucleic acid encoding such a recombinant protein.
Regarding claim 14, patented claim 20 requires a pharmaceutical composition comprising such a recombinant protein or the nucleic acid encoding such a recombinant protein, and a pharmaceutically acceptable carrier and/or diluent.
Regarding claim 15, patented claim 21 requires a method of treating a cancer.
Claims 1-10 and 14-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/267,282 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims anticipate the instant claims. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Reference claim 18 recites a designed ankyrin repeat domain with binding specificity for CD3 comprising any one of the amino acid sequences of SEQ ID NOs: 11 to 15. Reference SEQ ID NOs: 12-15 are identical to instant SEQ ID NOs: 1-4, respectively. This satisfies all of the limitations of instant claims 1-8 and inherently meets the functional limitations of claims 9-10 and 16-17.
Regarding claims 14-15, reference claim 15 requires a method of treating a disease.
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 12-14, 17-19, 25-26, 29, 43, 46, 51-53, 56, 59-60 of copending Application No. 18/281,152 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims anticipate the instant claims. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Reference claim 26 recites a designed ankyrin repeat domain with binding specificity for CD3 comprising any one of the amino acid sequences of SEQ ID NOs: 13 to 17. Reference SEQ ID NOs: 14-17 are identical to instant SEQ ID NOs: 1-4, respectively. This satisfies all of the limitations of instant claims 1-8 and inherently meets the functional limitations of claims 9-10 and 16-17.
Regarding claims 11 and 18, reference claim 25 requires that the designed ankyrin repeat is combined with at least one binding domain with specificity for a tumor-associated antigen.
Regarding claims 12 and 19, reference claim 43 requires a half-life extension domain that binds HSA.
Regarding claims 13 and 20, reference claim 51 requires a nucleic acid encoding such a recombinant protein.
Regarding claim 14, reference claim 56 requires a pharmaceutical composition.
Regarding claim 15, reference claim 59 requires a method of treating a disease.
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 9, 14-16, 18-27 of copending Application No. 18/281,156 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims anticipate the instant claims. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Reference claim 9 recites a recombinant binding protein comprising designed ankyrin repeat domain with binding specificity for CD3 comprising any one of the amino acid sequences with at least 85% identity to one of SEQ ID NOs: 55-59, combined with an ankyrin repeat domain with binding specificity for CD33. Reference SEQ ID NOs: 55-58 are identical to instant SEQ ID NOs: 1-4, respectively. This satisfies all of the limitations of instant claims 1-8, 11, and 18, and inherently meets the functional limitations of claims 9-10 and 16-17.
Regarding claims 12 and 19, reference claim 15 requires a half-life extension domain that binds HSA.
Regarding claims 13 and 20, reference claim 19 requires a nucleic acid encoding such a recombinant protein.
Regarding claim 14, reference claim 20 requires a pharmaceutical composition.
Regarding claim 15, reference claim 21 requires a method of treating a disease.
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 9, 14-16, 19-27 of copending Application No. 18/281,161 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims anticipate the instant claims. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Reference claim 9 recites a recombinant binding protein comprising designed ankyrin repeat domain with binding specificity for CD3 comprising any one of the amino acid sequences with at least 85% identity to one of SEQ ID NOs: 34-38, combined with an ankyrin repeat domain with binding specificity for CD123. Reference SEQ ID NOs: 34-38 are identical to instant SEQ ID NOs: 1-4, respectively. This satisfies all of the limitations of instant claims 1-8, 11, and 18, and inherently meets the functional limitations of claims 9-10 and 16-17.
Regarding claims 12 and 19, reference claim 15 requires a half-life extension domain that binds HSA.
Regarding claims 13 and 20, reference claim 19 requires a nucleic acid encoding such a recombinant protein.
Regarding claim 14, reference claim 20 requires a pharmaceutical composition.
Regarding claim 15, reference claim 21 requires a method of treating a disease.
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 9, 14-16, 19-27 of copending Application No. 18/554,248 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims anticipate the instant claims. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Reference claim 9 recites a recombinant binding protein comprising designed ankyrin repeat domain with binding specificity for CD3 comprising any one of the amino acid sequences with at least 85% identity to one of SEQ ID NOs: 55-59, combined with an ankyrin repeat domain with binding specificity for CD70. Reference SEQ ID NOs: 55-58 are identical to instant SEQ ID NOs: 1-4, respectively. This satisfies all of the limitations of instant claims 1-8, 11, and 18, and inherently meets the functional limitations of claims 9-10 and 16-17.
Regarding claims 12 and 19, reference claim 14 requires a half-life extension domain that binds HSA.
Regarding claims 13 and 20, reference claim 19 requires a nucleic acid encoding such a recombinant protein.
Regarding claim 14, reference claim 20 requires a pharmaceutical composition.
Regarding claim 15, reference claim 21 requires a method of treating a disease.
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19, 21-24 of copending Application No. 18/492,484 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims anticipate the instant claims. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Reference claim 7 recites a recombinant binding protein comprising designed ankyrin repeat domain with binding specificity for CD3 comprising any one of the amino acid sequences with at least 85% identity to one of SEQ ID NOs: 1-4, combined with an ankyrin repeat domain with binding specificity for CD33 and another for CD123. Reference SEQ ID NOs: 1-4 are identical to instant SEQ ID NOs: 1-4, respectively. This satisfies all of the limitations of instant claims 1-8, 11, and 18, and inherently meets the functional limitations of claims 9-10 and 16-17.
Regarding claims 12 and 19, the claims recite several proteins further comprising a half-life extension domain that binds HAS, as evidenced by the Sequence Table.
Regarding claims 13 and 20, reference claim 17 requires a nucleic acid encoding such a recombinant protein.
Regarding claim 14, reference claim 18 requires a pharmaceutical composition.
Regarding claim 15, reference claim 19 requires a method of treating a disease.
Conclusion
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/CHRISTINA BRADLEY/Primary Examiner, Art Unit 1654
Prosecution Insights