DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Claims 1-19 are pending upon entry of amendment filed on 6/28/23.
Applicant’s election of group I, claims 1-17 and 19 without traverse in the reply filed on 11/24/25 has been acknowledged.
Accordingly, claim 18 is withdrawn from further consideration by the examiner, 37 CFR 1.142 (b) as being drawn to a nonelected invention.
The current application contains one independent claim and the claimed invention drawn to a diluent for diluting a drug product wherein the diluent comprises buffer, one or more stabilizing or tonicity agents and the drug product comprises multispecific hetero-dimeric antibody with a first and second engineered CH3 domain.
Claims 1-17 and 19 are under consideration in the instant application.
3. Applicant’s IDS filed on 2/21/23 has been acknowledged.
4. The oath filed on 6/28/23 has been acknowledged.
5. Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d).
6. The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
7. 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.
8. Claims 8-10 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) is considered indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). Note the explanation given by the Board of Patent Appeals and Interferences in Ex parte Wu, 10 USPQ2d 2031, 2033 (Bd. Pat. App. & Inter. 1989), as to where broad language is followed by "such as" and then narrow language. The Board stated that this can render a claim indefinite by raising a question or doubt as to whether the feature introduced by such language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Note also, for example, the decisions of Ex parte Steigewald, 131 USPQ 74 (Bd. App. 1961); Ex parte Hall, 83 USPQ 38 (Bd. App. 1948); and Ex parte Hasche, 86 USPQ 481 (Bd. App. 1949). In the present instance, claims 5-10 recite being stable at 5oC, about 25oC and/or 40oC for at least 3 months which is the higher and lower temperature at the same time.
9. 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.
10. Claims 1 and 17 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.
Specifically, there is insufficient written description to demonstrate that Applicant was in possession of the claimed genus of diluents comprising multispecific hetero-dimeric antibody fragment thereof” and “at least 80% homology to the amino acid sequence of SEQ ID NO:1-9”, respectively.
The guidelines of the Examination of Patent Applications Under the 35 U.S.C. 112, §1 “Written Description” Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, or by disclosure of 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 genus (Federal Register, Vol. 66, No. 4, pages 1099-1111, Friday January 5, 2001, see specially page 1106 column 3, MPEP2163).
In The Reagents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F.3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted: A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the genus does, rather than what it is. See Fiers, 984F. 2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statue requires a description of an invention, not an indication of a result that might achieve if one made that invention. See In re Wilder 736 F.2d 1516,1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outline goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”). Accordingly, naming the type of material generally known to exist, in the absence of knowledge as to what that material consist of, is not a description of that material”.
The court has further stated that “Adequate written description requires a precise definition such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention”. Id. At 1566, 43 USPQ2d at 1404 (quoting at 1171, 25 USPQ2d at 1606). Also see (CAFC2002). Enzo-Biochem v. Gen-Probe Fiers, 984 F.2d 01-1230.
The instant claims are drawn to compositions comprising a huge genus of structurally distinct multispecific heterodimeric antibody fragments and the antibody comprising at least 80% sequence homologous to SEQ ID No:1-9 varying 233-723 amino acids in lengths. This would encompass any 20-145 amino acid modifications of the antibodies set forth in the SEQ ID NO:109 alone. Thus, claims would encompass structurally unrelated antibodies. There is no art recognized correlation between structure and function of such classes of the molecules. Although the prior art recognizes CD3xHER2 set forth in SEQ ID NO:1-3 seen in U.S. Pat. 9,493,563 or EGFR xCD3 seen in SEQ ID NO:5-9 in U.S. Pat. 12,351,602 used in treatment T cell related disorders, no multispecific heterodimeric antibody fragments and the antibody comprising at least 80% sequence homologous to SEQ ID No:1-9 used in such treatments. Although the specification discloses stability studies of AB1 and AB2 with D1-10 or C1-18, respectively, no multispecific heterodimeric antibody fragments and the antibody comprising at least 80% sequence homologous to SEQ ID No:1-9 are studied. The instant specification does not disclose a correlation between structure defined by “80% homologous” to the antibody set forth in SEQ ID NO:1-9. Further, the disclosed species are not sufficiently representative of the huge genus encompassed by the present claims. Thus, one of skilled in the art would conclude that the specification fails to provide adequate written description to demonstrate that Applicant was in possession of the claimed genus of the claimed pharmaceutical compositions. See Eli Lilly, 119 F, 3d 1559, 43, USPQ2d, 1398.
11. Claims 1 and 17 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for a diluent for drug product set forth in SEQ ID NO:1-9 comprising a buffer set forth in histidine, tris, citrate, phosphate or citrate-phosphate and a stabilizing agent set forth in polyol, amino acids, polysorbate or sodium chloride in isotonic solution, does not reasonably provide enablement for more.
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/or use of the invention commensurate in scope with these claims. Claims 1 and 17 recite “multispecific hetero-dimeric antibody fragment thereof” and “at least 80% homology to the amino acid sequence of SEQ ID NO:1-9”, respectively.
The specification does not enable one of skill in the art to practice the invention as claimed without undue experimentation. Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed.Cir.1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of the skilled in the art to practice the claimed invention.
There is insufficient guidance in the specification as filed as to how the skilled artisan would make and use “multispecific hetero-dimeric antibody fragment thereof “ or “at least 80% homology to the amino acid sequence of SEQ ID NO:1-9” of drug product without undue experimentation. Although substitutions of CH3 domain is suggested in claim 14, homology of at least 80% is not limited to CH3 domain. The currently amended claims are readable upon at least 80% “similar” (not even required identity) sequences of the claimed SEQ ID NO:1-9 and the fragments thereof.
Although Examples in the instant specification disclose various diluents exhibited in C1-18 or D1-10 with Ab1 evidenced by CD3xHER2 (note p. 30) or Ab2 evidenced by EGFRxCD3 (note p.34) may be depicted in SEQ ID NO:1-9, no other multispecific heterodimeric antibody fragments or at least 80% homologous to SEQ ID NO:1-9 are disclosed throughout the specification.
As such, given that the structures of the fragment and at 80% homologous to SEQ ID NO:1-9 is disclosed, stabilizing effects for the excipients shown as D1-10 or C1-18 dedicated to Ab1 evidenced by CD3xHER2 (note p. 30) or Ab2 evidenced by EGFRxCD3 cannot be extrapolated to any other structurally unrelated multispecific heterodimeric antibody fragments or at least 80% homologous to the claimed SEQ ID NO:1-9. The specification fails to provide sufficient guidance to direct a person of skilled in the art to make and achieve the intended use of the claimed invention without undue experimentation
To summarize, reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view or the quantity of experimentation necessary, the limited working example, the unpredictability of the art, the lack of sufficient guidance in the specification, and the breath of the claims, it would take undue trials and errors to practice the claimed invention.
12. 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 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.
13. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
14. Claim(s) 1-13, 15-16 and 19 is/are rejected under 35 U.S.C. 102(a)(1)(2) as being anticipated by U.S. Pub. 2019/0151448.
The ‘448 publication teaches pharmaceutical compositions comprising multispecific hetero-dimeric antibody readable upon drug product in the presence of buffer, amino acid and/or polysorbate at pH 5-6 (note claims, [0014-0036]). Further, the ‘448 publication teaches the multispecific heterodimeric antibody includes CD3 and second arms include HER2 and EGFR (claim 15-16) and modifications of the CH2-CH3 domain are recited (claims 1-3). IN addition, the diluent in item (iii) of claim 1 of the ‘448 publication exclude bispecific antibody and includes buffer set forth in citrate, phosphate, histidine and the stabilizer includes arginine, lysine, polysorbate and/or sodium chloride (claims 6-8). The pharmaceutical compositions are stable at 4oC for at least 24 months (p. 26).
In addition, the ‘448 publication teaches compositions are stored in solution (claim 28) or in infusion system (p.4-7), the infusion system includes saline solution (p. 6-7) inherently comprise NaCl ([0073]). Note the ‘448 publication teaches uninterrupted administration of antibody for 24 hours ([0348]) readable upon claimed infusion system. The limitation of “ the loss measured by ELISA before and after incubation in an infusion system is less than about 30%” is met as seen in Fig 8 (further p. 5). Note the recovery is less than 30% after the storage after at least 24 hours at 25oC ([0060]) and routine screening is done by ELISA ([103]). The recovery of greater than 90% seen in Fig 8A-C meets the claimed limitation.
Further, the specific excipient concentration of citrate or histidine buffer includes 5-20mM, amino acid including arginine or lysine salt of less than 100mM and polysorbate less than 0.004% ([376-380], [416]) and dilution scheme of 1:10 (Example 7) are taught.
As seen in the ‘448 publication, the pharmaceutical composition comprising heterodimeric antibody comprising CD3xEGFR, buffer comprising histidine or citrate in the presence of amino acid or excipient including saline at pH 5-6 are taught and meets the claimed limitations. Therefore, the reference teachings anticipate the claimed invention.
15. 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 of this title, 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
16. Claims 1-17 and 19 are rejected under 35 U.S.C. 103(a) as being unpatentable over U.S. Pub. 2019/0151448 in view of U.S. Pat. 9,493,563 and U.S. Pub 2020/0369747.
The teachings of the ‘448 publication have been discussed, supra.
The disclosure of the ‘448 publication differs from the instant claimed invention in that it does not teach the use of SEQ ID NO:1-9 as in claim 17 of the instant application.
The ‘563 patent teaches CD3x HER2 set forth in claimed SEQ ID NO:1-3 as seen in SEQ ID NO:47, 159-160 and this specific that also binds Protein A column so the purification is more efficient and effective (col. 3-5 and claims). Claim 14 is included in this rejection as having exact claimed SEQ ID NO:1-9 is expected to contain the specific substitutions.
Likewise, the ‘747 publication teaches that the antibody comprising the claimed SEQ ID NO:4-9 (note prior art SEQ ID NO:4-9) and the prior art antibody is more efficient in inactivating virus and make bulk purification process effective by reducing contaminants.
It would have been obvious to one of ordinary skill in the art at the time the invention was made to utilize prior art antibodies of known sequences as seen in the ‘563 patent and the ’747 publication into the diluent for multispecific heterodimer antibody taught by the ‘448 publication.
One of ordinary skill in the art at the time the invention was made would have been motivated to do so because the utilization of SEQ ID NO:1-9 would reduce purification burden by reducing contaminants and/or improve purification using protein A column.
From the teachings of references, it would have been obvious to one of ordinary skill in art to combine the teachings of the references and there would have been a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of the ordinary in the art at the time of invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
17. No claims are allowable.
18. Any inquiry concerning this communication or earlier communications from the examiner should be directed to YUNSOO KIM whose telephone number is (571)272-3176. The examiner can normally be reached Mon-Fri 8:30-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Yunsoo Kim
Patent Examiner
Technology Center 1600
December 19, 2025
/YUNSOO KIM/Primary Examiner, Art Unit 1641