DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s election without traverse of group I, claims 153-154, in the reply filed on 8/19/25 is acknowledged. Claims 155-158 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
Claims 153-154 are being acted upon.
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.
Claims 153-154 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 153 is indefinite in the recitation of a polypeptide comprising (a) an extended recombinant polypeptide comprising a barcode fragment (BAR) releasable from said polypeptide upon digestion by a protease, (b) a bispecific antibody construct (BsAB) and (c) a “release segment (RS)” positioned between said extended recombinant polypeptide and said bispecific antibody construct. The specification does not define the “release segment (RS)” and it is not clear what is encompassed. Is it a protease cleavable amino acid sequence? Would it encompass other types of structures, for example non-protein or chemical structures? What does it release? Is it intended to further limit the “releasable” polypeptide limitation of part (a). The scope of the claims is unclear.
Claim 153 is further indefinite in the recitation that the extended recombinant polypeptide is formed from a plurality of non-overlapping sequence motifs that are each from 9 to 14 amino acids in length, wherein said plurality of non-overlapping sequence motifs comprise a set of non-overlapping sequence motifs repeated at least two times. As an initial matter, if a sequence motif is repeated, it is unclear how it can also be formed of “non-overlapping” motifs, since repeated motifs would be comprised of overlapping residues. The scope of the non-overlapping motifs is unclear an indefinite. The specification exemplifies an extended recombinant polypeptide in, for example, SEQ ID NO: 8014:
SPAGSPTSTESGTSESATPESGPGTSTEPSEGSAPGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSTPAESGSETPGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSESATPESGPGSEPATSGSETPGTSESATPESGPGSPAGSPTSTEEGSPAGSPTSTEEGTSTEPSEGSAPGTSESATPESGPGTSESATPESGPGTSESATPESGPGSEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEGTSTEPSEGSAPGTSTEPSEGSAPGGSAP
In the above sequence, different 12 amino acids sequence portions or motifs are distinguished with shaded, italics, bold or various underlining. However, it is not clear what would make the plurality of motifs “non-overlapping”. For example, “GTS” appears in both of the first two motifs (highlighted in gray and a single underline), and these would therefore appear to be overlapping motifs, in that they both contain a common, overlapping sequence portion. It is not clear what would make the motifs “non-overlapping”. Does the non-overlapping mean non-identical? The scope of the claimed extended recombinant polypeptides cannot be established.
Claim 153 is also indefinite in that the polypeptide has at least 90% of its amino acids residues that are identified “herein” by glycine (G), Alanine (A), serine (S), threonine (T), glutamate (E) or proline (P). It is unclear what “”herein” refers to (the specification, the claims)? Do the claims simply mean that at least 90% of its amino acids are glycine (G), Alanine (A), serine (S), threonine (T), glutamate (E) or proline (P)? The reference to identified herein is unclear and indefinite.
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 153-154 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.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability in the art, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re wands, 858 F.2d 731, 737.8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Claims 153-154 require an extended recombinant polypeptide characterized by being (i) at least 100 or at least 150 amino acids, (ii) wherein 90% of the amino acids of the extended polypeptide are Gly, Ala, Ser, Thr, Glu or Pro, (iii) wherein the extended polypeptide comprises at least 4 amino acids selected from Gly, Ala, Ser, Thr, Glu or Pro, and (iv) the extended polypeptide is formed from a plurality of non-overlapping sequence motifs that are each 9 to 14 amino acids in length. The claim fails to qualify a functional property of the extended polypeptide with the structural requirements described in the claim. The specification teaches that in some cases the XTEN sequence can have a low amount of alpha-helix percentage from zero to less than 5% and a low amount of beta helix percentage from zero to less than 5% (page 93, paragraph [0182]) which doesn’t teach a major property of the resulting XTEN structure, but only teaches that the property of having a alpha helix or beta helix is low or absent. The specification does teach that in some embodiments, the XTEN sequence can have a high percentage of random-coil of at least 80% (page 93, paragraph [0182]). The specification teaches that the polypeptide has a terminal half-life that is at least two-fold longer compared to the bispecific antibody construct not linked to any XTEN. In certain embodiments, the polypeptide is less immunogenic compared to the bispecific antibody construct not linked to any XTEN, (paragraph [0031]) and a high hydrodynamic radius (page 94, paragraph [0187][). Podust et al (Journal of Controlled Release, 2016, Vol. 240, pp. 52-66) teach that the formation of random coil polymers by XTEN is essential for tuning the pharmacokinetic properties of the therapeutic payloads in a predictable manner (page 54, first column, lines 7-10).
Furthermore, the present claims require that the extended polypeptide functions in a manner to release the barcode fragment such that it has a molecular weight and sequence that differs from all other peptide fragments of the polypeptide, which would include the generic bispecific antibody portion, upon complete digestion of said polypeptide by any protease. As taught by Venkatraman, proteases exist as a wide range of structurally and functionally distinct enzymes with different specificity. Understanding substrate specificity is very complex and factors which effect cleavability include sequence specificity, accessibility, and location. Thus, providing for the claimed function of releasing the barcode fragment such that it has a molecular weight and sequence that differs from all other peptide fragments of the polypeptide, upon complete digestion of said polypeptide by any protease with the genus of sequences encompassed by the present claims would be highly unpredictable. The instant specification discloses several species of extended recombinant polypeptide in SEQ ID Nos: 8001-8020, wherein the peptides function as claimed after digestion with Glu-C protease, for example. However, this is not commensurate in scope with the instant claims which encompass a genus of structurally distinct sequences that release the barcode fragment such that it has a molecular weight and sequence that differs from all other peptide fragments of the polypeptide, upon complete digestion of said polypeptide by any protease. For example, all of the polypeptides in SEQ ID NO: 8001-8020 are comprised of amino acids A, G, S, T, E, and P, wherein the protease cleaves after E. However, the present claims do not even require that the polypeptide has any E residues, which is the basis of cleavage in the disclosed polypeptides. The present claims would encompass, for example, an extended polyepitope comprised of G, A, S, T, wherein a completely different protease than GluC cleaves the sequence in the manner claimed. Providing for the claimed function with the genus of different polypeptide sequences and proteases encompassed by the present claims would require an enormous amount of experimentation and would be highly unpredictable. Furthermore, the specification discloses certain species of VH/VL for both CD3 and Her2 binding arms, but the present claims encompass any VH/VL sequence for the HER 2 binding arm, for example. The claims also require that the BAR has a different molecular weight from all other peptide fragments releasable from the polypeptide, which would include those released from the genus of Her2 and CD3 binding arm portion. Determining which CD3 and Her2 binding arms would function in the manner claimed would also require considerable trial and error experimentation.
Furthermore, the claims encompass bispecific construct that binds CD3, with the minimum defined sequence being a single CDRH3 sequence of SEQ ID NO: 10 and any HER2 binding fragment, and the polypeptide must also function above to release the unique barcode upon digestion with any protease. The state of the art is such that the 6 CDRs of an antibody are critically involved in antigen binding, that even single amino acid changes can alter antigen specificity of binding, and that CDR mutations are unpredictable in terms of affinity, specificity, and solubility, and are also context dependent (see Hall, 1992, and Rabia, 2018). See also Chen which teaches that a single amino acid change in a CDR2 can abolish antigen binding, and that increasing the number of mutations dramatically influences loss of binding (See page 858, in particular). Thus, making and using the genus of antibody fragments that binds CD3 with the only defined structure being a single CDR3 would be highly unpredictable. The only species of CD3 binding antibodies disclosed in the instant specification that have SEQ ID NO: 10 or those that also have specifically defined CDRS from the constructs in Table 6b, i.e. SEQ ID NO: 1 or 2 for CDRL1, SEQ ID NO: 4 for CDRL2, SEQ ID NO: 6 for CDRL3, SEQ ID NO: 8 for CDRH1 and SEQ ID NO; 9 for CDRH2. This is not commensurate in scope with the instant claims, and the no guidance is provided in the instant specification regarding which other VL or CDRH sequences can be used with SEQ ID NO: 10 to provide for CD3 binding.
Thus, given the breadth of the claims, the lack of guidance provided by the instant specification, and the unpredictability of the art, it would require undue experimentation to make and use the polypeptides as broadly claimed.
Claims 153-154 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, 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. See MPEP 2163.
The present claims encompass a genus of structurally distinct polypeptides comprising an extended polypeptide that functions to release a barcode fragment such that it has a molecular weight and sequence that differs from all other peptide fragments of the polypeptide, which would include the generic bispecific antibody portion, upon complete digestion of said polypeptide by any protease. As taught by Venkatraman, proteases exist as a wide range of structurally and functionally distinct enzymes with different specificity. Understanding substrate specificity is very complex and factors which effect cleavability include sequence specificity, accessibility, and location. Thus, providing for the claimed function of releasing the barcode fragment such that it has a molecular weight and sequence that differs from all other peptide fragments of the polypeptide, upon complete digestion of said polypeptide by any protease with the genus of sequences encompassed by the present claims would be highly unpredictable. The instant specification discloses several species of extended recombinant polypeptide in SEQ ID Nos: 8001-8020, wherein the peptides function as claimed after digestion with Glu-C protease, in combination with specific VH/VL sequences of CD3/Her2 binding arms. However, these are not sufficiently representative of the broad genus of structurally distinct polypeptides claimed which do not even require the presence of any E amino acids, which is the basis of cleavage for Glu-C. The present claims encompass a genus of structurally distinct extended polypeptides comprising 4 types of amino acid residues selected from G, A, S, T, E, or P, that are cleaved by any protease, any a genus of VH/VL, and the species discloses are not representative, nor does the specification disclose a correlation between structure and function as broadly claimed.
Furthermore, the claims encompass bispecific construct that binds CD3, with the minimum defined sequence being a single CDRH3 sequence of SEQ ID NO: 10 and any HER2 binding fragment, and the polypeptide must also function above to release the unique barcode upon digestion with any protease. The state of the art is such that the 6 CDRs of an antibody are critically involved in antigen binding, that even single amino acid changes can alter antigen specificity of binding, and that CDR mutations are unpredictable in terms of affinity, specificity, and solubility, and are also context dependent (see Hall, 1992, and Rabia, 2018). See also Chen which teaches that a single amino acid change in a CDR2 can abolish antigen binding, and that increasing the number of mutations dramatically influences loss of binding (See page 858, in particular). Thus, making and using the genus of antibodies or antibody fragments that binds a genus of different specific antigen with the only defined structure being a single CDR3 would be highly unpredictable. The specification does not disclose a correlation between structure and function of binding CD3 for the genus of CD3 binding arms encompassed by the present claims, nor does it disclose a representative number of species. The only species of CD3 binding antibodies disclosed in the instant specification that have SEQ ID NO: 10 are those that also other specifically defined CDRS from the constructs in Table 6b, i.e. SEQ ID NO: 1 or 2 for CDRL1, SEQ ID NO: 4 for CDRL2, SEQ ID NO: 6 for CDRL3, SEQ ID NO: 8 for CDRH1 and SEQ ID NO; 9 for CDRH2. This is not sufficiently representative of the broad genus of different CD3 antibody binding fragments encompassed by the present claims.
The instant application has not provided a sufficient description showing possession of the necessary 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 of polypeptides and antigen binding fragments encompassing various structures, specificities and functions. Further, the Court has interpreted 35 U.S.C. §112, first paragraph, to require the patent specification to “describe the claimed invention so that one skilled in the art can recognize what is claimed. Enzo Biochem, Inc. v. Gen-Probe Inc, 63 USPQ2d 1609 and 1618 (Fed. Cir. 2002).
In evaluating whether a patentee has fulfilled this requirement, our standard is that the patent’s “disclosure must allow one skilled in the art ‘to visualize or recognize the identity of’ the subject matter purportedly described.” Id. (quoting Regents of Univ. of Cal. v. Eli Lilly & Co., 43 USPQ2d 1398 (Fed Cir. 1997)).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Also, it is noted that the Court has held that the disclosure of screening assays and general classes of compounds was not adequate to describe compounds having the desired activity: without disclosure of which peptides, polynucleotides, or small organic molecules have the desired characteristic, the claims failed to meet the description requirement of § 112. See University of Rochester v. G.D. Searle & Co., lnc., 69 USPQ2d 1886,1895 (Fed. Cir. 2004).
Meeting the written description threshold requires showing that the applicant was in “possession” of the claimed invention at the time of filing. Vas-Cath, 935 F.2d at 1563-1564. Support need not describe the claimed subject matter in exactly the same terms as used in the claims. Eiselstein v. Frank, 52 F.3d 1035, 1038 (Fed. Cir. 1995). This support cannot be based on obviousness reasoning – i.e., what the written description and knowledge in the art would lead one to speculate as to modifications the inventor might have envisioned, but failed to disclose. Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997). Ariad points out, the written description requirement also ensures that when a patent claims a genus by function, the specification recites sufficient materials to accomplish that function - a problem that is particularly acute in biological arts." Ariad, 598 F.3d at 1352-3. Note the following Court Decisions regarding the written description of antibodies in the context of the current claims.
Thus, one of skill 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. See Eli Lilly, 119 F. 3d 1559, 43, USPQ2d 1398.
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 153-154 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 12,215,156. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘156 patent claims a polypeptide comprising SEQ ID NO: 34, which inherently comprises an extended recombinant polypeptide comprising a barcode fragment with all of the limitations of the present claims, and a bispecific antibody construct comprising a CD3 antigen bind fragment with a CDR-H3 of SEQ ID NO: 10 of the instant application, and a second antigen binding fragment that binds to HER2, and a release segment position between said extended recombinant polypeptide and the bispecific antibody construct. Thus, the polypeptide of SEQ ID NO: 34 claimed in the ‘156 patent is a species falling within the generic polypeptides claimed in the instant application. The ‘156 patent further claims a pharmaceutical composition comprising said polypeptide and a pharmaceutically acceptable excipient.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY E JUEDES whose telephone number is (571)272-4471. The examiner can normally be reached on M-F from 7am to 3pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Dan Kolker, can be reached at telephone number 571-272-3181. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Amy E. Juedes
Patent Examiner
Technology Center 1600
/AMY E JUEDES/Primary Examiner, Art Unit 1644
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