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 .
Status of the Claims
Claims 1 – 20 were pending. Claims 1 – 2, 6 and 9 – 13 have been amended; claims 17 – 20 have been canceled; and claims 21 – 23 have been newly added. Claims 1 – 16 and 21 – 23 are currently pending and are the subject of this Office Action.
OBJECTIONS/REJECTIONS WITHDRAWN
Specification
The specification was objected to because of the use of the term “nanobody”.
In view of the amendments to the specification in the reply of 03/30/2026, this objection is withdrawn.
Drawings
The drawings were objected to because Fig. 6 includes text and symbols that are illegible and must be modified so that they are clear.
In view of the amendments to the drawings in the reply of 03/30/2026, this objection is withdrawn.
Claim Objections
Claim 6 was objected to because of informalities.
In view of the amendments to claim 6 in the reply of 03/30/2026, this objection is withdrawn.
Claim Rejections - 35 USC § 112
Claim 2 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.
In view of the amendments to claim 2 in the reply of 03/30/2026, this rejection is withdrawn.
Claim Rejections - 35 USC § 102
Claims 1 – 3, 9 – 10, 14, and 16 – 20 were rejected under 35 U.S.C. 102(a)(1) as being anticipated by KUFER (WO , published 02/04/2016; see PTO-892: Notice of References Cited).
In view of the claim amendments in the reply of 03/30/2026, this rejection is withdrawn.
REJECTIONS MAINTAINED IN MODIFIED FORM
Claim Rejections - 35 USC § 103
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 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claims 1 – 12, 14 – 16 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over KUFER.
KUFER is directed to a bispecific single chain antibody construct binding to a target cell surface antigen via a first binding domain and to the T cell surface antigen CD3 via a second binding domain, the construct comprising (a) a first FcRn binding peptide comprises the amino acid sequence QRFVTGHFGGLX1PANGS whereas X1 is Y or H (see claim 1 of KUFER). Thus, KUFER teaches the sequence of SEQ ID NO: 1 of present claim 1 or, more specifically, of SEQ ID NO: 5 of present claim 3. KUFER’s SEQ ID NO: 3 (in KUFER’s claims 2 – 3) is identical to present SEQ ID NO: 5. See Appendix (alignment with SEQ ID NO: 5).
KUFER teaches that "antibody constructs" includes monovalent, bivalent and polyvalent / multivalent constructs and, thus, monospecific constructs, specifically binding to only one antigenic structure, as well as bispecific and polyspecific / multispecific constructs, which specifically bind more than one antigenic structure, e.g. two, three or more, through distinct binding domains. See KUFER at p. 4, fourth paragraph.
Thus, KUFER renders the limitations of claims 1 and 3 obvious.
At the effective filing date of the present claims, it would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of KUFER. The artisan would have been motivated to make and use the polypeptide of present claims 1 and 3 because KUFER teaches that the fusion of short terminal peptide extensions binding to the neonatal Fc receptor (FcRn) extends the half-live of those proteins by making use of the FcRn-mediated recycling and transcytosis system (see KUFER at Detailed description of the Invention, p. 3). Thus, the artisan would have a reasonable expectation of success from the teachings of KUFER.
Regarding claims 2 and 9, KUFER teaches that the disclosed antibody constructs may be fragments of full-length antibodies, such as VH, VL or modified fragments of antibodies, also called antibody variants, such as scFv. See p. 5, first paragraph.
According to the present specification, “FIG. 1 shows a schematic representation of FcRn binding polypeptide modified scFvs. VL indicates variable light domain; VH indicates variable heavy domain; L represents linker (also shown as unlabeled boxes flanking linker peptides); Cyc indicates cyclic peptide; Lin indicates linear peptide; and Alb indicates albumin peptide” (paragraph 14 of the pre-grant publication).
KUFER teaches that the antibody constructs may be modified fragments of antibodies or may have a structure such as (VH-VL-CH3)2 (see p. 5, first paragraph). KUFER further teaches that the FcRn binding peptide at the N-terminus comprises the amino acid sequence QRFCTGHFGGLHPCNG (which teaches the present SEQ ID NO: 1) and the one at the C-terminus comprises the amino acid sequence QRFVTGHFGGLHPANG (identical to present SEQ ID NO: 5) (see KUFER’s claim 1).
In addition to the VH and VL domains taught by KUFER (discussed above), KUFER also teaches domains binding to albumin which are of linear structure (see p. 33, top paragraph) and cyclic peptides (see p. 32, third paragraph from the bottom).
KUFER teaches that “it has been surprisingly found that cyclic peptides, i.e. peptides comprising a cys-loop, are on the one hand critical for the production e.g. in the cell culture (upstream production criteria) and the isolation of bispecific single chain constructs (downstream production criteria). On the other hand, the example shows that the position of such cyclic peptide within the protein chain is decisive to the production and isolation of bispecific single chain constructs. The bispecific single chain antibody constructs of the invention comprising the identified combinations of FcRn binding peptides at the N-terminus and at the C-terminus of the construct allow the provision of an antibody construct with preferred tissue distribution characteristics while retaining their industrially acceptable upstream and downstream production criteria” (see p. 32, third paragraph from the bottom).
Therefore, KUFER teaches the domains of FIG. 1 of the present specification and that the antibody constructs and the positioning of the domains may be engineered according to multiple factors such as tissue distribution and production efficiency.
Thus, it would have been obvious to arrive the structures of parts (a) – (d) of present claim 4 by routine experimentation of the connectivity of the domains taught by KUFER. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05 (I) and (II).
Regarding claims 5 – 6, KUFER teaches an antibody construct with two FcRn binding peptides (see KUFER’s claim 1), and KUFER teaches a sequence identical to SEQ ID NO: 5 (see KUFER’s SEQ ID NO: 3 in KUFER’s claims 2 – 3 and Appendix).
Regarding claim 7, KUFER teaches an antibody construct with two FcRN binding sites, each having the sequence of SEQ ID NO: 5 (see KUFER’s claim 3(d): KUFER’s SEQ ID NO: 3 is identical to present SEQ ID NO: 5 of the present application). Thus, KUFER renders part (p) of present claim 7 obvious.
Regarding claim 8, KUFER teaches that antibodies on which the constructs are based on humanized and human antibodies. See p. 4, fourth paragraph.
Regarding claim 10, KUFER teaches a nucleic acid molecule encoding the antibody construct and a vector comprising said nucleic acid molecule. See abstract.
Regarding claim 11, KUFER teaches a nucleic acid molecule encoding the antibody construct. See abstract.
Regarding claim 12, KUFER teaches a pharmaceutical composition comprising an antibody construct (see KUFER’s claim 18), and teaches that the formulations and compositions thus may be designed in accordance with the invention for delivery by any suitable route of administration (see p. 51, first paragraph). Thus, KUFER’s pharmaceutical composition would have an excipient appropriate for the administration of the pharmaceutical composition.
Regarding claim 14, KUFER teaches that the disclosed antibody construct is used in the prevention, treatment or amelioration of a disease selected from a proliferative disease, a tumorous disease, a viral disease or an immunological disorder and that treatment includes the application or
administration of the formulation to the body, an isolated tissue, or cell from a patient who
has a disease/disorder, a symptom of a disease/disorder, or a predisposition toward a
disease/disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate,
improve, or affect the disease, the symptom of the disease, or the predisposition toward the
disease.(see p. 49, second to last paragraph – p. 50, first paragraph).
Regarding claim 15, KUFER teaches a method for the treatment or amelioration of a proliferative disease, a tumorous disease, a viral disease or an immunological disorder (see KUFER’s claim 20) and that the formulations and compositions thus may be designed in accordance with the invention for delivery by any suitable route of administration (see p. 51, first paragraph).
Regarding claim 16, KUFER teaches present SEQ ID NO:1 (QRFX1TGHFGGLX2PX3NG) in KUFER’s claim 1 (KUFER’s SEQ ID NO: 1). Furthermore, KUFER teaches the fusion of short terminal peptide extensions binding to FcRn in a strategy to modify a recombinant protein in order to extend the half-live of that protein by making use of the FcRn-mediated recycling and transcytosis system (see p. 3, Detailed description of the Invention in KUFER), which indicates that KUFER’s antibody construct is recombinant and not naturally occurring.
Regarding claim 21, KUFER teaches a method for the treatment or amelioration of a proliferative disease, a tumorous disease, a viral disease or an immunological disorder (see KUFER at claim 20) and a pharmaceutical composition comprising an antibody construct (see KUFER at claim 18).
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over KUFER as applied to claims 1 – 12, 14 – 16 and 21 and further in view of PLAVEC (Plavec, T.V., et al. Engineering of lactic acid bacteria for delivery of therapeutic proteins and peptides. Appl Microbiol Biotechnol 103, 2053–2066 (2019); see PTO-892).
The teachings of KUFER are discussed above and fully incorporated here.
PLAVEC is directed to lactic acid bacteria (LAB), which have a long-term history of use in food industry and are becoming attractive for use in therapy on account of their safety, intrinsic beneficial health effects, and considerable biotechnological potential. PLAVEC teaches LAB as vectors for delivery of various therapeutic molecules and can be used for the treatment or prevention of numerous conditions: inflammatory bowel diseases, infections, autoimmune diseases, and even cancer. See abstract.
Regarding claim 13, PLAVEC reviews the use of LAB, with the emphasis on the most commonly used genera Lactococcus and Lactobacillus, for the delivery of therapeutic proteins and peptides. See abstract.
Thus, because KUFER teaches the isolated polypeptide of present claim 4 (a therapeutic protein) and PLAVEC teaches that bacteria may be used to deliver therapeutic proteins, it would have been obvious to use PLAVEC’s bacteria to arrive to the pharmaceutical composition of present claim 13.
At the effective filing date of the present claims, it would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of KUFER and PLAVIC. The artisan would have been motivated to make and use the inventions of claim 13 because KUFER teaches that the fusion of short terminal peptide extensions binding to the neonatal Fc receptor (FcRn) extends the half-live of those proteins by making use of the FcRn-mediated recycling and transcytosis system (see KUFER at Detailed description of the Invention, p. 3) and PLAVIC teaches that LAB as vectors for delivery of various therapeutic molecules and can be used for the treatment or prevention of numerous conditions: inflammatory bowel diseases, infections, autoimmune diseases, and even cancer. Thus, the artisan would have a reasonable expectation of success from the teachings of KUFER and PLAVIC.
Claims 22 – 23 are rejected under 35 U.S.C. 103 as being unpatentable over KUFER as applied to claims 1 – 12, 14 – 16 and 21 and further in view of PATEL (Patel, A., Bah, M.A. & Weiner, D.B. In Vivo Delivery of Nucleic Acid-Encoded Monoclonal Antibodies. BioDrugs 34, 273–293 (2020); see PTO-892: Notice of References Cited submitted with this Office Action).
The teachings of KUFER are discussed above and incorporated here. Although KUFER teaches the isolated peptide of present claim 1, from which claims 22 – 23 indirectly depend from, KUFER does not expressly teach the limitation of new claims 22 – 23.
PATEL is directed to nucleic acid delivery of antibody employing synthetic plasmid DNA vector platforms, and RNA delivery, these being important approaches that are advancing simple, rapid, in vivo expression and having an impact in animal models of infectious diseases and cancer, among others. See PATEL at the abstract.
At the effective filing date of the present claims, it would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of KUFER and PATEL. The artisan would have been motivated to make and use the inventions of claims 22 - 23 because KUFER teaches that the fusion of short terminal peptide extensions binding to the neonatal Fc receptor (FcRn) extends the half-live of those proteins by making use of the FcRn-mediated recycling and transcytosis system (see KUFER at Detailed description of the Invention, p. 3) and PATEL teaches that nucleic acid delivery of antibody are advancing simple, rapid, in vivo expression and having an impact in animal models of infectious diseases and cancer, among others . Thus, the artisan would have a reasonable expectation of success from the teachings of KUFER and PATEL.
Response to Arguments
On p. 9, third paragraph from the bottom, Applicant argues that “Kufer does not teach or suggest and polypeptides comprising a FcRn binding polypeptide of SEQ ID NO:1 and a single specific binding moiety or SEQ ID NO:8. Because Kufer does not teach or suggest all elements of the claims it cannot anticipate the claims. Applicant respectfully requests withdrawal of the objection.”
Applicant’s argument is not persuasive because KUFER renders present claim 1 obvious as discussed above.
On p. 9, last paragraph, Applicant argues that “[t]he Office asserts that given Kufer one of ordinary skill in the art could arrive at the instant claims through routine optimization. The Examiner has not satisfied the burden of establishing a prima facie case of obviousness based upon routine optimization.” On p. 10, second paragraph – p. 11, first paragraph, Applicant further argues that “If a proposal for modifying the prior art to arrive at the instant claims causes the prior art to become inoperable or destroys its intended function, then the requisite motivation to make the modification does not exist. See In re Fritch, 972 F.2d 1260, 1265 n.12. . . In the instant case, Kufer teaches bispecific single chain antibody constructs comprising: a first binding domain that specifically binds to a target cell surface antigen; a second binding domain that specifically binds to T cell surface antigen; and two separate FcRn binding peptides. Kufer teaches that ‘[t]he present invention relates to a bispecific single chain antibody construct binding to a target cell surface antigen via a first binding domain and to the T cell surface antigen CD3 via a second binding domain, the construct comprising two FcRn binding peptides.’ See Field of Invention. Kufer additionally states that ‘antibody constructs according to the invention comprise specificities for at least two different antigens or targets.’ See paragraph [0063]. If the constructs of Kufer were altered to include only a single binding domain, then the construct would not be able to bind to the target cell surface antigen and the T cell surface antigen CD3 rendering the constructs inoperable and unsuitable for their purpose. Therefore, the proposed modification of Kufer is inappropriate because a proposed modification cannot render the construct unsuitable for its purpose.”
Applicant’s argument has been considered but not found persuasive because KUFER teaches the domains of structures of the FIG. 1 of the present application (VL, VH and linker). Although KUFER teaches bispecific antibodies, KUFER still renders obvious the claimed a single specific binding moiety obvious because KUFER teaches that “the term ‘antibody constructs’ includes monovalent, bivalent and polyvalent / multivalent constructs and, thus, monospecific constructs, specifically binding to only one antigenic structure, as well as bispecific and polyspecific / multispecific constructs, which specifically bind more than one antigenic structure, e.g. two, three or more, through distinct binding domains.” See KUFER at p. 5, second paragraph. Furthermore, KUFER teaches “a trifuncional molecule as described for Catumaxomab, which is able to recruit a further cell type via the Fc-FcR function” (see KUFER at p. 2, first paragraph). Catumaxomab has a structure with only one FcRn-binding polypeptide, such as that of the claimed isolated polypeptide of present claim 1. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)”. See MPEP 2144.05 (I) and (II). Because KUFER teaches all the limitations of present claim 1, KUFER renders the claimed isolated polypeptide obvious.
Conclusion
No claim is allowed.
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 Estella Gustilo whose telephone number is (703)756-1706. The examiner can normally be reached Monday - Friday 9:30 AM - 5:30 PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gregory Emch can be reached at 571-272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ESTELLA M. GUSTILO/Examiner, Art Unit 1646
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
APPENDIX
Alignment with SEQ ID NO: 5
RESULT 1
BCL90154
(NOTE: this sequence has 26 duplicates in the database searched.
See complete list at the end of this report)
ID BCL90154 standard; peptide; 16 AA.
XX
AC BCL90154;
XX
DT 24-MAR-2016 (first entry)
XX
DE Linear FcRn binding peptide H, SEQ ID 3.
XX
KW FcRn binding peptide; Neonatal Fc receptor binding peptide;
KW antibody production; antibody therapy; cancer; cytostatic;
KW immune disorder; immunomodulator; neoplasm; prophylactic to disease;
KW recombinant protein; therapeutic; viral infection; virucide.
XX
OS Unidentified.
XX
CC PN WO2016016415-A1.
XX
CC PD 04-FEB-2016.
XX
CC PF 31-JUL-2015; 2015WO-EP067627.
XX
PR 31-JUL-2014; 2014US-0031777P.
XX
CC PA (AMGE-) AMGEN RES MUNICH GMBH.
XX
CC PI Kufer P, Hoffmann P, Munz M, Klinger M, Dopfer E, Nahrwold E;
XX
DR WPI; 2016-08993X/16.
XX
CC PT New bispecific single chain antibody construct capable of specifically
CC PT binding to target cell surface antigen and T cell surface antigen used in
CC PT composition for preventing, treating or ameliorating e.g. viral disease.
XX
CC PS Claim 2; SEQ ID NO 3; 252pp; English.
XX
CC The present invention relates to a novel bispecific single chain antibody
CC construct binding to a target cell surface antigen via a first binding
CC domain and to a T cell surface antigen CD3 via a second binding domain,
CC useful for preparing a pharmaceutical composition for preventing,
CC treating or ameliorating proliferative disease, tumorous disease, viral
CC disease or immunological disorder. The construct comprises two neonatal
CC Fc receptor (FcRn) binding peptides, wherein (a) a first FcRn binding
CC peptide comprises the amino acid sequence of SEQ ID NO:1 (see BCL90152),
CC and (b) a second FcRn binding peptide comprises the amino acid sequence
CC of SEQ ID NO:4 (see BCL90155). The invention further provides: (1) a
CC polynucleotide encoding the antibody construct; (2) a vector comprising
CC the polynucleotide; (3) a host cell transformed or transfected with the
CC polynucleotide or with the vector; (4) a process for producing the
CC antibody construct; (5) a pharmaceutical composition comprising the
CC antibody construct; (6) a method for preventing, treating or ameliorating
CC proliferative disease, tumorous disease, viral disease or immunological
CC disorder, by administering the antibody construct to a subject; and (7) a
CC kit comprising the antibody construct, the vector, and/or the host cell.
CC The present sequence represents a FcRn binding peptide, which is used in
CC the bispecific single chain antibody construct either at the N-terminus
CC or C-terminus, where the construct is used in the pharmaceutical
CC composition for preventing, treating or ameliorating proliferative
CC disease, tumorous disease, viral disease or immunological disorder.
XX
SQ Sequence 16 AA;
Query Match 100.0%; Score 92; Length 16;
Best Local Similarity 100.0%;
Matches 16; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QRFVTGHFGGLHPANG 16
||||||||||||||||
Db 1 QRFVTGHFGGLHPANG 16
Prosecution Insights