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 .
Application Status
This action is written in response to applicant’s correspondence received on 7/2/2026. Claims 16-17, 19-26, and 28-31 are pending. Claims 16-17, 19, 23, 25, and 28 have been amended. Claims 18 and 27 have been cancelled. All pending claims are currently under examination.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow. This Office Action is Final.
Claim Rejections - 35 USC § 112 – New Matter Rejection/New Rejection Necessitated by Amendment
Claims 16-17, 19-26, and 28-31 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. This is a New Matter rejection.
Regarding claim 16, claim 16 recites method steps of producing a second antigen-binding molecule, where the active method steps comprise immunizing a mammal with a first antigen and first antigen-binding molecule in a complex (step i), selecting a group of cells which produce monoclonal antibodies against the complex of first antigen/antigen-binding molecule where the monoclonal antibody binds with higher affinity to the complex as opposed to the individual components of the complex (step ii), and selecting from the population of cells that make monoclonal antibodies a cell which enhances the binding affinity of the first antigen to the first antigen-binding molecule (step iii). Steps b-c involve culturing the cell producing the monoclonal antibody and purifying the second antigen-binding molecule from the supernatant. Newly added claim limitations at the end of step (c) of claim 16 recite that the first antigen-binding molecule is an antibody or fragment of an antibody, and furthermore, that “the second antigen-binding molecule has multiple antigen-binding specificity and further binds to a second antigen,” (final line of claim 16).
The specification defines “bispecific antibodies” as antibodies which bind to two or more different antigens per antibody molecule (see paragraph 5). Thus, claim 16 is reciting that the second antigen-binding molecule has multiple antigen-binding specificity and binds a second antigen, claim 16 presently recites that the second antigen-binding molecule is a “bispecific antibody” per the specification at paragraph 5.
Thus, claim 16 as a whole is reciting a method where the only steps are to immunize a mammal, screen monoclonal antibody populations, where one of which contains a second antigen-binding molecule which is bispecific. Claim 16 relies upon the mammal itself to naturally produce a bispecific antibody (the second antigen binding molecule). This claim language is problematic because it is not a method which was performed in the specification. For example, Example 3 of the specification describes the identification and culturing of monoclonal antibody-producing cells (see paragraphs 112-113). In a separate process, FAE technology is used to produce bispecific antibodies, using the monoclonal antibodies and the genes encoding them as starting material (see paragraphs 114-116). Thus, the mammals which are immunized do not produce bispecific antibodies (“multiple-binding specificity and further binds a second antigen,” final line of claim 16), but rather are monoclonal antibodies which bind a single epitope. The presently recited method was therefore not taught in the specification.
Claims 17 and 19-22 depend from claim 16 and do not resolve this issue and are therefore also rejected.
Independent claim 23 suffers from a similar new matter rejection. Claim 23 recites an additional screening method, where the screening method to determine a second antigen-binding molecule is instead performed using a molecule display library (e.g., phage display as recited in claim 24). Claim 23, similar to claim 16, recites that the second antigen-binding molecule produced by the method steps is “has multiple antigen-binding specificity and further binds to a second antigen (final line of claim 23). The specification defines “bispecific antibodies” as “binding to two or more different antigens per antibody molecule,” (paragraph 5). Thus, claim 23 recites a method of screening to identify an antigen-binding molecule, where the screening method alone yields a bispecific antibody. This claim language is problematic because it is not a method which was performed in the specification. For example, Example 7 details a method of identifying and harvesting antibodies which are specific for a complex of adenosine-antibody using phage display (Example 7, paragraphs 142-143). However, the second antigen-binding molecule (i.e., antibody which binds to the adenosine-antibody complex) is not a bispecific antibody as presently required by the claim, but is instead an antibody which binds only the complex. Bispecific antibodies which recognize the adenosine/antibody complex and for instance CD3 were formed using a separate method as described in Example 3 (i..e, FAE technology, paragraph 157 of the specification). Thus, during the library screening process, the process does not yield bispecific antibodies, as the method is presently recited.
Claims 24-26 and 28-31 depend from claim 23 and do not resolve this issue and are therefore also rejected.
Enablement – New Rejection Necessitated by Amendment
Claims 16-17, 19-26, and 28-31 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.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Wands states, on page 1404:
Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They 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 these in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
Nature of the Invention/Breadth of the Claims
Regarding claim 16, claim 16 recites method steps of producing a second antigen-binding molecule, where the active method steps comprise immunizing a mammal with a first antigen and first antigen-binding molecule in a complex (step i), selecting a group of cells which produce monoclonal antibodies against the complex of first antigen/antigen-binding molecule where the monoclonal antibody binds with higher affinity to the complex as opposed to the individual components of the complex (step ii), and selecting from the population of cells that make monoclonal antibodies a cell which enhances the binding affinity of the first antigen to the first antigen-binding molecule (step iii). Steps b-c involve culturing the cell producing the monoclonal antibody and purifying the second antigen-binding molecule from the supernatant. Newly added claim limitations at the end of step (c) of claim 16 recite that the first antigen-binding molecule is an antibody or fragment of an antibody, and furthermore, that “the second antigen-binding molecule has multiple antigen-binding specificity and further binds to a second antigen,” (final line of claim 16). The specification defines “bispecific antibodies” as antibodies which bind to two or more different antigens per antibody molecule (see paragraph 5). Thus, claim 16 is reciting that the second antigen-binding molecule has multiple antigen-binding specificity and binds a second antigen, claim 16 presently recites that the second antigen-binding molecule is a “bispecific antibody” per the specification at paragraph 5. Claim 16 is therefore broadly drawn to a method where the practitioner immunizes an antibody/antigen complex, identifies cells which produce monoclonal antibodies against the complex, where the monoclonal antibodies are also bispecific antibodies.
This claim language is problematic because 1) the specification has not reduced this method to practice commensurate in scope with what is claimed and 2) it is known in the art that immunized mammals do not produce monoclonal antibodies which are bispecific, as presently recited in the claim. Thus, there is a high degree of unpredictability with respect to whether or not the recited method could be practiced or used because it is not likely that such a method would work (see discussion of state of the art, below).
Similarly, independent claim 23 recites a method of identifying, selecting, and culturing cells to make a supernatant to make a second antigen-binding molecule, where the molecule is selected based upon a molecule display library, where furthermore the second antigen-binding molecule is recited to have “multiple antigen-binding specificity and further bind to a second antigen.” This claim language is problematic because 1) this is not a method performed by the Applicant in the speciciation, where the molecule library display screening yields a bispecific antibody and 2) the state of the art casts doubt upon the reliability of the method as recited.
Guidance in the Specification
Regarding the guidance provided in the specification, the Applicant offers Examples 1-19. For instance, regarding the method of claim 16, the Applicant offers Example 3 as a method of producing the second antigen-binding molecule (see paragraphs 112-116). Example 3 of the specification describes the identification and culturing of monoclonal antibody-producing cells (see paragraphs 112-113). In a separate process, FAE technology is used to produce bispecific antibodies, using the monoclonal antibodies and the genes encoding them as starting material (see paragraphs 114-116). Thus, the mammals which are immunized do not produce bispecific antibodies (“multiple-binding specificity and further binds a second antigen,” final line of claim 16), but rather are monoclonal antibodies which bind a single epitope. The presently recited method was therefore not taught in the specification.
Regarding claim 23, Example 7 details a method of identifying and harvesting antibodies which are specific for a complex of adenosine-antibody using phage display (Example 7, paragraphs 142-143). However, the second antigen-binding molecule (i.e., antibody which binds to the adenosine-antibody complex) is not a bispecific antibody as presently required by the claim, but is instead an antibody which binds only the complex. Bispecific antibodies which recognize the adenosine/antibody complex and for instance CD3 were formed using a separate method as described in Example 3 (i..e, FAE technology, paragraph 157 of the specification). Thus, during the library screening process, the process does not yield bispecific antibodies, as the method is presently recited.
State of the Art
Regarding the state of the art, it is known in the art that monoclonal antibodies, such as those produced in the active steps recited in claim 16, target a single antigen. For instance, AbCam (Instructional information concerning antibodies published by AbCam, a recognized commercial leader in antibody technology, published 5/282025), is instructional material published concerning different types of antibodies (Title, Abstract, and throughout). AbCam teaches that:
“Monoclonal antibodies (mAbs) are immunoglobulins derived from a single B cell clone that recognize one specific epitope, while bispecific antibodies (bsAbs) are engineered molecules designed to simultaneously bind two distinct epitopes or antigens through separate paratopes within one construct,” (page 1, final paragraph).
Thus, AbCam, a commercial producer of antibodies and recognized industrial expert, teaches that monoclonal antibodies such as those produced by the method derived from single B cell clones recognize one specific epitope whereas bispecific antibodies are engineered separately to bind two distinct epitopes (above). As such, the knowledge of the art that a specific cell line producing a single monoclonal antibody will bind to one specific epitope casts doubt on the efficacy or feasibility of using the method as presently recited because it is known that a mammal immunized using the recited method will produce monoclonal antibodies which are not bispecific (above).
Additionally, with respect to using screening methods such as phage display to identify/generate bispecific antibodies, as presently recited in claim 23, it is known in the art that such library screening methods as phage display have issues with identifying bispecific antibodies. For instance, Fagete (US 10,689,461 B2, published 5/17/2018) teaches that:
“While antibody phage display has been used to discover bispecific antibodies to date, the process has not streamlined to insure that selection is based on co-engagement. Moreover, other techniques known in the art (e.g., phage diabody technology) have not been used for direct selection based on co-engagement and broader application of phage diabody technology may not be possible due to difficulties in constructing diabody repertoires. Differences in the antigen binding site geometry of diabodies versus immunoglobulin molecules may compromise their utility for translation into immunoglobulin-based bispecific antibody formats. Thus, there exists a need for phage display compositions and methods that allow for pairs of antibodies to be coselected based on co-engagement of their respective targets,” (column 1, paragraphs 4-5)
Thus, while Fagete teaches that it may be possible to identify bispecific antibodies using library screening methods such as phage display, it is known in the art that there is a high degree of uncertainty with respect to the selection being based upon co-engagement, where further phage diabody technologies may not be possible in such screenings (above). Further, Fagete teaches that it is known in the art that there is a need to develop new phage display compositions and methods which allow for antibody selection based upon coselection and co-engagement of their targets (above). Fagete, a post-filing publication, therefore teaches that at the time of filing phage display to identify/capture bispecific antibodies such as those presently recited was highly unpredictable, where furthermore novel methods would be required to address the known issues associated with such phage display libraries and their use with bispecific antibodies and diabodies (above). The Applicant did not address these known issues, or reduce the recited method to practice.
Undue Experimental Burden
As discussed above, the art teaches that it is highly unpredictable and not feasible to use the methods as presently recited because 1) immunizing mammals to generate monoclonal antibody populations does not yield bispecific antibodies as presently recited and 2) phage library display methods and their use with bispecific antibody development and identification are known to be problematic with art-recognized deficiencies. The practitioner is therefore met with undue experimental burden because they would be required to develop new methods or solve known methodological issues in the art which the Applicant offers no guidance to or addresses in order to practice the recited method.
Response to Arguments
The Applicant’s arguments filed 7/2/2026 have been considered but are not persuasive. With respect to the present state of the Application, it is noted that the art rejection is not herein reiterated. The lack of inclusion of the prior art rejection is not a concession that the Applicant’s arguments have overcome the art rejection. Rather, the Applicant’s amendments have altered the claim scope in a manner which does not read on the prior art rejection, nor do the present claims reflect the methods performed by the Applicant (see New Matter rejection, above). Additionally, the practitioner is not enabled to practice the methods as recited for the reasons given above. As such, the new rejections are given in response to the present requirements of the claim limitations per the Applicant’s amendments, where the prior art rejections are not conceded but simply do not read on the present claim limitations. Presently, the claims have been amended in a manner which does not appear to align with the spirit or scope of the invention (see 112(a) rejections, above).
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DOUGLAS CHARLES RYAN whose telephone number is (571)272-8406. The examiner can normally be reached M-F 8AM - 5PM.
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/D.C.R./Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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