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 .
DETAILED ACTION
Election/Restrictions
Applicant’s election with traverse of Group I, claims 1-7, 9, 14-16, and 19-22 and species: SEQ ID NO: 1 as the recombinant binding protein sequence, CD3 as the immune cell binding moiety, SEQ ID NO: 36 as the CD3 binding moiety, SEQ ID NO: 32 as the sequences for the HAS binding moiety, acute myeloid leukemia as the type of cancer in the reply filed 05/07/2026 is acknowledged. The traversal is on the ground(s) that Li et al. 2019 does not negate the special technical feature as it does not disclose the specific binding properties. This is not found persuasive because the sequences for the CD123 ankyrin domains are not fully defined in the instant claims and are left broad and unbound by complete structural detail. As such Li et al., reads on the broad description encompassed in the instant claims. Additionally, the product and methods are different statutory categories of invention and as such can be split into groups for examination.
Claims 23-27 are withdrawn from consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions and species, there being no allowable generic or linking claims. Election was made in the reply filed 05/07/2026.
The requirement is still deemed proper and is therefore made FINAL.
Claims 1-7, 9, 14-16, and 19-22 are now under consideration in the instant Office Action.
Claim Rejections - 35 USC § 112
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 3 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.
Instant claim 3 recites the term “optionally”. The phrase “optionally” is interpreted as "for example" which renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. For the purposes of examination, the instant claims will be interpreted without the optional limitations as they are not required or claimed as necessary to the invention.
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 1-7, 9, 14-16, and 19-22 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.
The claims are drawn to recombinant binding proteins comprising an ankyrin
repeat domain with binding specificity for cluster of differentiation 123 (CD123). Claims 1-7, 9, 14-16, and 19-22 are drawn to ankyrin repeat domains comprising an ankyrin repeat module having an amino acid sequence selected from SEQ ID NOs: 12 to 30 and 58 to 59, and sequences in which up to 9 amino acids in any of SEQ ID NOs: 12 to 30 and 58 to 59 are substituted by another amino acid. Claim 2 is drawn to ankyrin repeat domains with at least 85% identity to SEQ ID NO: 1- to 9 and 55 to 57.
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. 31). 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. 30). Each module is 33 amino acids in length and contains a b-turn, two antiparallel a-helices and a loop. Figure 1 from Binz (in instant PTO-892) 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):
PNG
media_image1.png
284
670
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Greyscale
to yield (Figure 1c):
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media_image2.png
248
491
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Greyscale
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 CD123. Thus, to satisfy the written description requirement the specification must provide sufficient information to distinguish ankyrin repeat domain sequences that bind to CD123 with specificity from those that do not bind to CD123.
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 in SEQ ID NOs: 12 to 30 and 58 to 59, as well as DARPin proteins in SEQ ID NOs: 55 to 57.
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 CD123 binding as well. The scope of the CD123 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: 12 to 30 and 58 to 59, and DARPin proteins in SEQ ID NOs: 55 to 57 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.
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.
As stated above, the complete structure of ankyrin repeat modules SEQ ID NOs: 12 to 30 and 58 to 59, and DARPin proteins in SEQ ID NOs: 55 to 57 are disclosed. The amino acid sequences of these species are insufficient to suggest how the selected design ankyrin repeat domains (DARPins) bind to CD123. The specification does not present the structure of one of these species bound to CD123. The Examiner is not aware of a structure of an ankyrin repeat protein bound to CD123 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 CD123 and a correspond structure-activity analysis.
The specification asserts that proteins having at least 85% identity to SEQ ID NOs: 1 to 9 and 55 to 57 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 NOs: 1 to 9 and 55 to 57, 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 CD123 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: 12 to 30 and 58 to 59 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).
The specification states that the ankyrin repeat domains that bind CD123 comprise a repeat module with the ankyrin repeat sequence SEQ ID NOs: 12 to 30 and 58 to 59 and sequences wherein up to 9 amino acids in any of SEQ ID NOs: 12 to 30 and 58 to 59 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 CD123. Therefore, this formula does not constitute a partial structure of the claimed genus.
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 CD123 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 CD123 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.
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 CD123.
As stated previously, the specification does not present the structure of one SEQ ID NOs:
34 to 38 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.
The specification discloses an empirical method for identifying ankyrin repeat domains
that bind to CD123. 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 CD123.
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 CD123. 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.
Claims 1-7, 9, 14-16, and 19-22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a recombinant binding protein with fully defined sequences SEQ ID NOs: 12 to 30 and 55 to 59, does not reasonably provide enablement for any recombinant binding protein comprising an ankyrin repeat domain specific for human CD123. 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.
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 CD123 engagers and their use in immune cell activation.
The breadth of the claims
The claims are drawn to ankyrin repeat domains with at least 85% identity to SEQ ID NOs: 1 to 9 and 55 to 57. Although this limitation may appear to be narrow, up to 15% 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 CD123.
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 medical conditions implicating the immune system is high.
The Level of Guidance in the Specification
The specification does not provide any working examples that are specific to the immune cell activation that is listed in the instant claims. Examples 5-8 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: 34 to 38 are combined with ankyrin repeat domains that bind the tumor-associated antigen, CD123. 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 CD123-binding ankyrin domains work with domains that bind other tumor-associated antigens. In addition, it is not clear if the CD123-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 T-cell engager 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.
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 1-7, 9, 14-16, and 19-22 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. 18/267,608 (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.
Instant 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. Instant SEQ ID NOs: 34-38 are identical to reference’s SEQ ID NOs: 1-4, respectively. This satisfies all of the limitations of instant claims 1-2, 6-7, 9, and inherently meets the functional limitations of claims 3-5 and 22.
Regarding instant claims 14-16, reference claim 12 and 19 requires a half-life extension domain that binds HSA.
Regarding instant claims 19, reference claim 13 and 20 requires a nucleic acid encoding such a recombinant protein.
Regarding instant claim 20, reference claim 14 requires a pharmaceutical composition.
Regarding instant claim 21, reference claim 15 requires a method of treating a disease.
Claims 1-7, 9, 14-16, and 19-22 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. Instant SEQ ID NOs: 55-58 are identical to reference’s SEQ ID NOs: 1-4, respectively. This satisfies all of the limitations of instant claims 1-2, 6-7, 9, and inherently meets the functional limitations of claims 3-5 and 22.
Regarding instant claims 14-16, reference claim 12 and 19 requires a half-life extension domain that binds HSA.
Regarding instant claims 19, reference claim 13 and 20 requires a nucleic acid encoding such a recombinant protein.
Regarding instant claim 20, reference claim 14 requires a pharmaceutical composition.
Regarding instant claim 21, reference claim 15 requires a method of treating a disease.
Claims 1-7, 9, 14-16, and 19-22 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: 1-5, 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 1-2, 6-7, 9, and inherently meets the functional limitations of claims 3-5 and 22.
Regarding instant claims 14-16, reference claim 12 and 19 requires a half-life extension domain that binds HSA.
Regarding instant claims 19, reference claim 13 and 20 requires a nucleic acid encoding such a recombinant protein.
Regarding instant claim 20, reference claim 14 requires a pharmaceutical composition.
Regarding instant claim 21, reference claim 15 requires a method of treating a disease.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SELAM BERHANE whose telephone number is (571)272-6138. The examiner can normally be reached Monday - Friday, 9-5.
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/SELAM BERHANE/Examiner, Art Unit 1675
/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675
Prosecution Insights