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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-11) and the below listed species in the reply filed on 05/29/2026 is acknowledged. For the species within Group I, Applicant elected the conjugate comprising (i) an antibody H01L03 (corresponding to SEQ ID NOs: 1 and 7 for the heavy and light chain variable region respectively) and (ii) a radionuclide Lu-177.
However, the reply filed on 05/29/2026 failed to elect the peptide linker (see claim 10) and chelate site (see claim 11) for the conjugate. During a telephone conversation with Attorney Jason Kuchar on 08/19/2026, a provisional election was made without traverse to prosecute the invention of the species for the conjugate in addition to the antibody and radionuclide specified above comprising (i) a peptide linker comprising SEQ ID NO: 10 wherein the variable amino acid residue is lysine and (ii) a chelate agent shown in the following formula for L1-5:
PNG
media_image1.png
454
896
media_image1.png
Greyscale
.
Affirmation of this election must be made by applicant in replying to this Office action.
Claim Status
Claims 13-16 are cancelled. Claims 1-12 and 17-20 are pending. Claims 6, 12, and 17-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-5 and 7-11 are currently under consideration for patentability under 37 CFR 1.104.
Priority
This application is a 371 of PCT/JP2022/018413 (filed on 04/21/2022) which claims benefit of Japan Application No. JP2021-072201 (filed on 04/21/2021). Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Applicant cannot rely upon the certified copy of the foreign priority application because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
Because an English translation of the certified copy of the foreign priority application has not been made of the record, the examiner cannot establish whether or not what is claimed in the instant application was properly disclosed in the foreign priority application. Therefore, the benefit to the foreign priority application date is not granted.
Claims 1-11 have an effective filing date of 04/21/2022 corresponding to PCT/JP2022/018413.
Information Disclosure Statement
The information disclosure statement(s) filed on 03/11/2024, 02/24/2026, 04/27/2026, and 09/01/2026 has/have been considered. Signed copies are enclosed. All references considered unless marked with strikethrough.
Notably, the disclosure statements filed list Search Reports. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Claim Objections
Claims 5 and 9-11 are objected to because of the following informalities:
Claim 5: the extra space after “comprising” in line 3 should be deleted.
Claim 9: “sitespecifically” should be replaced with “site specifically”.
Claim 10: the extra spaces (i) before and after “peptide” in line 2, (ii) before the colon in line 5, (iii) after “Xaa1” in line 16, and (iv) after “modified with” in line 25 should be deleted.
Claim 10: “an integer of from one to five” should be replaced with “an integer from one to five”.
Claim 10: “consists of from 13 to 17 amino acids” should be replaced with “consists of 13 to 17 amino acids”.
Claim 11: “wherein in R11” should be replaced with “wherein R11”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
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, 4-5, and 7-11 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 MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application, including “the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention” (MPEP 2163[II][A][2]).
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, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, 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 Applicants were in possession of the claimed genus.
Claim 1 is drawn to a conjugate comprising a radionuclide that emits beta rays and a humanized antibody that specifically binds to MUC5AC, wherein the heavy and light chain variable regions consist of amino acid sequences having at least 95% sequence identity to SEQ ID NOs: 1-8. This claim language encompasses a genus of variants of anti-MUC5AC antibodies wherein up to 5% variation can occur in the VH and VL (including the CDRs).
The instant application teaches anti-MUC5AC antibodies with different combinations of SEQ ID NOs: 1-4 for the VH (¶ 0044) and SEQ ID NOs: 5-8 for the VL (¶ 0045) with 100% sequence identity (see also example 1, ¶ 0188), wherein SEQ ID NOs: 1-8 have conserved CDRs. The instant specification contemplates VH and VL sequences with up to 5% sequence variation as recited in the claims. However, the instant specification does not teach variation within the CDRs themselves. There is insufficient evidence of possession of invention regarding structure of the anti-MUC5AC antibody variants as claimed.
The recitation of up to 5% amino acid substitutions can occur in the VH, VL, and CDRs of the anti-MUC5AC antibody. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proc. Natl. Acad. Sci. USA, 79(6):1979-1983, March 1982). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function. Colman (Research in Immunology, 145:33-36, 1994) teaches that even a very conservative substitution within the interface of the antigen-binding region of the antibody, i.e. anywhere in the VH and VL, may abolish binding or may have very little effect on the binding affinity (Pg. 35, top of left column; Pg. 33, right column). These teachings indicate that amino acid substitutions both inside and outside of CDRs can completely change the antigen recognition of the antibody.
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or by describing structural features common the genus that “constitute a substantial portion of the genus.” See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997): “A description of a genus of cDNAs may be achieved by means of a recitation of a representative number of cDNA, defined by nucleotide sequence, falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus.” The Federal Circuit has recently clarified that a DNA molecule can be adequately described without disclosing its complete structure. See Enzo Biochem, Inc. V. Gen-Probe Inc., 296 F.3d 1316, 63 USPQ2d 1609 (Fed. Cir. 2002). The Enzo court adopted the standard that the written description requirement can be met by “show[ing] that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristic, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. “ Id. At 1324, 63 USPQ2d at 1613”. The court has since clarified that this standard applies to compounds other than cDNAs. See University of Rochester v. G.D. Searle & Co., Inc., F.3d,2004 WL 260813, at *9 (Fed.Cir.Feb. 13, 2004).
The instant specification fails to provide sufficient descriptive information in the broadly claimed variants of the anti-MUC5AC antibody. The specification does not provide specific or detailed structural characteristics of the variants with up to 5% amino acid substitutions in the sequences nor is it clear if the functions of said variants are retained. Thus, one of skill in the art would reasonably conclude that the inventor(s), at the time the application was filed, did not have possession of the claimed invention.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed' ”. The courts have decided: The purpose of the “written description” requirement is broader than to merely explain how to “make and use”; the 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.
As stated in the Written Description Guideline (2008), the levels of the skill and knowledge in the art would not be able to identify without further testing which of these variants could perform the same function (i.e. binding to MUC5AC) as the sequences for the anti-MUC5AC antibody as recited in claim 1. Based on the lack of knowledge and predictability in the art those of ordinary skill in the art would not conclude that the applicant was in possession of the claimed genus of antibody variants having the function listed in the claim based on the limited examples given in the instant specification.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “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). As discussed above, the skilled artisan cannot envision the detailed chemical structure(s) and functional attribute(s) of the encompassed genus of variants of the antibody as claimed, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, only anti-MUC5AC antibodies comprising sequences having 100% identity to the sequences recited in claim 1, but not the full breadth of the claims, meets the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
The specification does not reasonably convey possession of the subject matter of claim 1. Claim 1 fails to comply with the written description requirement of 35 U.S.C. 112(a) as a person having ordinary skill in the art cannot reasonably conclude that the applicant had possession of the claimed invention at the time the instant application was filed. Claims 4-5 and 7-11 are included in this rejection as they incorporate and/or depend on claim 1.
It is noted that claims 2-3 teaches SEQ ID NOs: 1-8 with 100% sequence identity. Therefore, claims 2-3 are not included in this rejection as they meet the written description requirement.
Claim Rejections - 35 USC § 112(b)
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 2-3 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.
Regarding claims 2-3, the phrases "SEQ ID NO: 1 (H01)”, "SEQ ID NO: 2 (H02)”, "SEQ ID NO: 3 (H03)”, "SEQ ID NO: 4 (H04)”, "SEQ ID NO: 5 (L01)”, "SEQ ID NO: 6 (L02)”, "SEQ ID NO: 7 (L03)”, and "SEQ ID NO: 8 (L04)” render the claims indefinite because it is unclear whether the limitations in the parentheses of the phrases are part of the claimed invention. See MPEP § 2173.05(d).
For the purposes of claim interpretation, the limitations in the parentheses will not be treated as part of the claimed invention.
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.
Claims 1, 4-5, and 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over WO2013157105A1 (published 2013-10-24, hereinafter referred to as WO ‘105; IDS filed 2024-03-11, Cite No. 15) in view of WO2019125982A1 (published 2019-06-27, hereinafter referred to as WO ‘982).
Regarding the antibody of instant claim 1, WO ‘105 teaches “mucin subtype 5 AC-specific humanized antibodies” (Pg. 1, line 10) comprising SEQ ID NOs: 12 and 15 for the heavy and light variable regions respectively (Fig. 1a, VH-5 is SEQ ID NO: 12; Fig. 1b, VL-1 is SEQ ID NO: 15). SEQ ID NOs: 12 and 15 of WO ‘105 have at least 95% sequence identity to instant SEQ ID NOs: 1 and 8 respectively. This teaching reads on a humanized antibody that specifically binds to mucin subtype 5AC and comprises amino acid sequences having at least 95% sequence identity to instant SEQ ID NOs: 1 and 8.
WO ‘105 further teaches the antibody is “labeled with an isotope (e.g.9 0 Y,1 1 1 In, etc.)” (Pg. 7, line 285) i.e. a radionuclide.
WO ‘105 does teach the radionuclide is lutetium-177 (instant claims 4 and 7), a chelating agent (instant claim 5), nor the number of chelating agents per antibody (instant claim 8). These deficiencies are remedied by WO ‘982.
Regarding the radionuclide of instant claim 1 and instant claim 4, WO ‘982 teaches “radiolabeled antibodies” (Abstract), specifically using the radionuclide “Lutetium-177 (177Lu), which emits… medium- energy beta-irradiation suitable for radiotherapy” (Pg. 2, lines 11-12). This teaching reads on the radionuclide that emits beta rays (instant claim 1) is lutetium-177 (instant claim 4).
Regarding instant claims 5 and 7, WO ‘982 further teaches lutetium-177 is a “radiometal ion” (Pg. 16, line 20; instant claims 5 and 7). This teaching reads on the radionuclide is the metal (instant claim 5) lutetium-177 (instant claim 7). WO ‘982 further teaches the chelating agent shown below comprising a chelate site and chelate linker (Pg. 18, structure of formula (II), referred to as DOTA-GA-DBCO; annotated to show chelate site and chelate linker; instant claims 5).
[AltContent: arrow][AltContent: textbox (Chelate site)][AltContent: textbox (Chelate linker)]
PNG
media_image2.png
188
308
media_image2.png
Greyscale
DOTA-GA-DBCO is identical to the elected species for the chelating agent, referred to as L1-5 in the instant application. This teaching reads on the chelating agent comprises a chelate linker and chelate site (instant claim 5). This teaching also reads on the structure of the chelating agent as delineated in instant claim 11 (see subsequent 103 rejection for how instant claim 11 is rendered obvious).
Regarding instant claim 8, WO ‘982 further teaches “labeling a polypeptide with two or more radiometal ions” (Pg. 19, lines 3-4) using a chelating agent wherein the polypeptide is an antibody. This teaching reads on the conjugate includes 2 molecules of the chelating agent per 1 molecule of the antibody (i.e. the polypeptide that is radiolabeled).
WO ‘982 further teaches “177Lu-labeled peptides demonstrate reduced normal tissue damage, and that 177Lu-labeling makes it possible to use a single radiolabeled agent for both therapy and imaging” (Pg. 2, lines 12-14), giving motivation for using the lutetium-117-bound chelating agents to produce advantageous radiolabeled antibodies.
WO ‘982 does not teach the sequences of the mucin subtype 5AC antibody of instant claim 1. This deficiency is remedied by WO ‘105.
The radionuclide lutetium-177 bound to a chelating agent was known and used prior to the effective filing date of the application. In addition, both WO ‘105 and WO ‘982 are in analogous arts (i.e. radiolabeled antibodies). Since WO ‘982 teaches lutetium-177-bound chelating agents can be used to create advantageous radiolabeled antibodies as they produce less damage to normal tissues, making them suitable for both therapeutics and labeling, there is motivation for using lutetium-177 bound to a chelating agent (e.g. DOTA-GA-DBCO) as taught by WO ‘982 in the mucin subtype 5AC antibody as taught by WO ‘105 to produce a more advantageous conjugate that is less likely to pose harm in a patient.
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The teaching, suggestion, or motivation in the prior art (i.e. WO ‘982 teaches lutetium-177-bound chelating agents can be used to create advantageous radiolabeled antibodies as they produce less damage to normal tissues, making them suitable for both therapeutics and labeling) would have led one of ordinary skill to modify the prior art reference (i.e. the mucin subtype 5AC antibody as taught by WO ‘105 is modified with lutetium-177 bound to a chelating agent) to arrive at the claimed invention. There is a reasonable expectation of success as the radionuclide lutetium-177 bound to a chelating agent (e.g. DOTA-GA-DBCO) was known and used prior to the effective filing date of the application. WO ‘105 expressly identifies its mucin subtype 5AC antibody can be modified with radioisotopes, applicable to lutetium-177. In addition, both WO ‘105 and WO ‘982 are in analogous arts (i.e. radiolabeled antibodies).
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to use lutetium-177 bound to a chelating agent (e.g. DOTA-GA-DBCO) as taught by WO ‘982 in the mucin subtype 5AC antibody as taught by WO ‘105 to produce a more advantageous conjugate that is less likely to pose harm in a patient.
Claims 9-11 are rejected under 35 U.S.C. 103 as being unpatentable over WO2013157105A1 (published 2013-10-24, hereinafter referred to as WO ‘105; IDS filed 2024-03-11, Cite No. 15) in view of WO2019125982A1 (published 2019-06-27, hereinafter referred to as WO ‘982) as applied to claims 1 and 5 above, and further in view of US20180141976A1 (published 2019-03-12, hereinafter referred to as US ‘976) as evidenced by Kishimoto et al. (Site-Specific Chemical Conjugation of Antibodies by Using Affinity Peptide for the Development of Therapeutic Antibody Format. Bioconjugate Chem. 20 March 2019; 30 (3): 698-702).
WO ‘105 and WO ‘982 are as discussed above and incorporated by reference herein. As fully described in the previous 103 rejection section, WO ‘105 and WO ‘982 collectively teach a conjugate comprising a radionuclide that emits beta rays, an antibody, and a chelating agent (instant claims 1 and 5; the chelating agent structure of instant claim 11). WO ‘105 and WO ‘982 do not teach the chelating agent specifically modifies an Fc region of the antibody via a peptide linker (instant claim 9) nor the peptide linker comprises SEQ ID NO: 10 wherein the variable amino acid residue is lysine (instant claim 10; the peptide linker of instant claim 11 as it depends on instant claim 10). These deficiencies are remedied by US ‘976 as evidenced by Kishimoto et al.
Regarding instant claim 9, US ‘976 teaches “an IgG-binding peptide” (Abstract) that “binds to the Fc domain of IgG” (¶ 0242) of an antibody. US ‘976 further teaches the peptide can be modified with “radioisotopes (such as… a chelate complex of a radioisotope metal ion, for example, a chelate complex of DOTA or desferoxamine). This teaching reads on the chelating agent (i.e. a chelate complex of a radioisotope metal ion) specifically modifies an Fc region of the antibody via a peptide linker (i.e. an IgG-binding peptide).
Regarding the antibody modification peptide and antibody modification linker of instant claim 10, US ‘976 further teaches the peptide comprises SEQ ID NO: 2 (GPDCAYHXGELVWCTFH) wherein “Xaa1 is a lysine residue:” (¶ 0221), which is identical to the elected species for the peptide linker i.e. instant SEQ ID NO: 10 wherein the variable amino acid residue is lysine. This teaching reads on the antibody modification peptide has the following characteristics:
Xa = GPD wherein a = 3;
Xaa1 = C i.e. an amino acid having a thiol group in its side chain;
Xb = AYH wherein b = 3;
Xaa2 = K;
Xc = GELVW wherein c = 5;
Xaa3 = C i.e. an amino acid having a thiol group in its side chain;
Xd = TFH wherein d =3; and
a + b + c + d = 14.
US ‘976 further teaches “DSG [disuccinimidyl glutarate]-modified N-terminally azidated IgG-binding peptide (Azide-PEG4-GPDCAYHXGELVWCTFH (SEQ ID NO: 2), wherein X represents DSG-modified lysine, the two Cys residues formed an intramolecular SS bond, and the C terminus was amidated)” (¶ 0310). This teaching reads on Xaa1 and Xaa3 (i.e. the two Cys residues) are linked through their side chains and the peptide linker comprises the antibody modification linker derived from the structure:
PNG
media_image3.png
74
273
media_image3.png
Greyscale
,
wherein n = 4 (i.e. Azide-PEG4). US ‘976 further teaches this construct was crosslinked to an IgG (Example 9, entire ¶ 0310).
Regarding instant claim 11, the structure of the chelating agent is taught by WO ‘982 but is included in this rejection as it depends on instant claim 10.
US ‘976 further teaches “[v]arious compounds linked to the IgG-binding peptide of the present invention can be added to IgG Fc via the IgG-binding peptide in a short time and with few side reactions” (¶ 0329), providing motivation for using the IgG-binding peptide as it is an easy and quick way to attach a compound in a site-specific manner.
US ‘976 does not teach a conjugate comprising a radionuclide that emits beta rays, an antibody, and a chelating agent (instant claims 1 and 5; the chelating agent structure of instant claim 11). This deficiency is remedied by WO ‘105 and WO ‘982. In addition, US ‘976 does not explicitly state the structure of the crosslinking agent (instant claim 10). This deficiency is remedied by Kishimoto et al.
Regarding the structure of the crosslinking agent of instant claim 10, Kishimoto et al. teach the DSG crosslinker produces the final structure of -CO(CH2)3CO- when bound to lysines (Pg. 699, Fig. 1b, depicts DSG crosslinker after reacting with proteins). Therefore, the DSG-modified lysine of US ‘976 when reacted with the lysine of IgG would inherently have the final structure of -CO(CH2)3CO- as delineated in instant claim 10 (i.e. the crosslinking agent) as evidenced by Kishimoto et al.
IgG-binding peptides were known and used prior to the effective filing date of the application. In addition, both WO ‘105, WO ‘982, and US ‘976 are in analogous arts (i.e. radiolabeled antibodies). Since US ‘976 teaches the IgG-binding peptide is an easy and quick way to attach a compound in a site-specific manner to an antibody, there is motivation for using the IgG-binding peptide as taught by US ‘976 to modify the lutetium-177-bound chelating agent and the mucin subtype 5AC antibody as taught by WO ‘982 and WO ‘105 to produce a more advantageous conjugate the IgG-binding peptide is added specifically to not interfere with antigen binding.
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The teaching, suggestion, or motivation in the prior art (i.e. US ‘976 teaches the IgG-binding peptide is an easy and quick way to attach a compound in a site-specific manner to an antibody) would have led one of ordinary skill to modify the prior art reference (i.e. the lutetium-177-bound chelating agent and the mucin subtype 5AC antibody as taught by WO ‘982 and WO ‘105 is modified with the IgG-binding peptide as taught by US ‘976) to arrive at the claimed invention. There is a reasonable expectation of success as IgG-binding peptides were known and used prior to the effective filing date of the application. US ‘976 expressly identifies their IgG-binding peptides can be used in conjunction with radiolabeled chelating agents and antibodies. In addition, both WO ‘105, WO ‘982, and US ‘976 are in analogous arts (i.e. radiolabeled antibodies).
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to use the IgG-binding peptide as taught by US ‘976 to modify the lutetium-177-bound chelating agent and the mucin subtype 5AC antibody as taught by WO ‘982 and WO ‘105 to produce a more advantageous conjugate the IgG-binding peptide is added specifically to not interfere with antigen binding.
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 1-5 and 7-11 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 and 18 of U.S. Patent No. 11369701 (hereinafter referred to as Pat. ‘701) in view of WO2013157105A1 (published 2013-10-24, hereinafter referred to as WO ‘105; IDS filed 2024-03-11, Cite No. 15), WO2019125982A1 (published 2019-06-27, hereinafter referred to as WO ‘982), and US20180141976A1 (published 2019-03-12, hereinafter referred to as US ‘976) as evidenced by Kishimoto et al. (Site-Specific Chemical Conjugation of Antibodies by Using Affinity Peptide for the Development of Therapeutic Antibody Format. Bioconjugate Chem. 20 March 2019; 30 (3): 698-702).
WO ‘105, WO ‘982, US ‘976, and Kishimoto et al. are as discussed above and incorporated by reference herein.
Instant claims 1-5 and 7-11 are rendered obvious by the combined teachings of the prior art as fully described in the 103 rejection section, the 103s being incorporated here. The addition of the patented claims over above over related subject matter only further supported this obviousness.
The instant claims teach a conjugate comprising an antibody, chelating agent, peptide linker, and a radionuclide that emits beta rays. Instant claim 1 teaches a conjugate comprising a radionuclide that emits beta rays and an anti-MUC5AC antibody with the VH and the VL having at least 95% sequence identity to instant SEQ ID NOs: 1-8. Instant claims 2-3 teaches VH and the VL comprising instant SEQ ID NOs: 1-8. Instant claims 4 and 7 teach various radionuclides. Instant claim 5 teaches a chelating agent comprising a chelate linker and chelate site. Instant claim 8 teaches the number of chelating agents per antibody. Instant claim 9 teaches the chelating agent modifies the Fc region of the antibody via a peptide linker. Instant claim 10 teaches a crosslinking agent and various peptide linkers. Instant claim 11 teaches various chelate sites.
The claims of Pat. ‘701 teach a conjugate comprising an antibody, chelating agent, peptide linker, and a radionuclide Zr-89. Claims 1-2 and 18 of Pat. ‘701 teach a humanized antibody specifically that binds to mucin subtype 5AC (MUC5AC) comprising SEQ ID NOs: 1-4 and SEQ ID NOs: 5-8 for the heavy and light chain variable regions respectively. SEQ ID NOs: 1-8 of Pat. ‘701 are identical to instant SEQ ID NOs: 1-8 respectively as recited in instant claims 1-3. Claims 1 and 8 of Pat. ‘701 teach a chelating agent comprising a chelate linker and chelate site as recited in instant claim 5. Claim 1 and 18 of Pat. ‘701 teaches the chelating agent modifies the Fc region of the antibody via a peptide linker as recited in instant claim 9 and the identical peptide formula as recited in instant claim 10. Claims 3-4 and 9-12 of Pat. ‘701 teach particular peptide linker sequences that are species of the genus of peptide linkers recited in instant claim 10. Claims 1 and 5-12 of Pat. ‘701 teach particular chelate site structures that are species of the genus of chelate sites recited in instant claim 11.
The claims of Pat. ‘701 do not teach (i) a radionuclide that emits beta rays (instant claim 1), specifically lutetium-177 (instant claims 4 and 7), (ii) the number of chelating agents per antibody (instant claim 8), nor (iii) a crosslinking agent (instant claim 10). These deficiencies are remedied by WO ‘105, WO ‘982, US ‘976, and Kishimoto et al.
The radionuclide lutetium-177 bound to a chelating agent and IgG-binding peptides were known modifications to antibodies, applicable to anti-mucin subtype 5AC, and used prior to the effective filing date of the application. In addition, WO ‘105, WO ‘982, US ‘976, and Pat. ‘701 are in analogous arts (i.e. radiolabeled antibodies). Since (i) WO ‘982 teaches lutetium-177-bound chelating agents can be used to create advantageous radiolabeled antibodies as they produce less damage to normal tissues, making them suitable for both therapeutics and labeling, and (ii) US ‘976 teaches the IgG-binding peptide is an easy and quick way to attach a compound in a site-specific manner to an antibody, there is motivation for using a lutetium-177-bound chelating agent and IgG-binding peptide (containing the crosslinking agent) as taught in WO ‘105, WO ‘982, and US ‘976 in in a radiolabeled mucin subtype antibody as taught by Pat. ‘701 to produce a more advantageous conjugate that is less likely to pose harm in a patient and wherein the IgG-binding peptide is added specifically to not interfere with antigen binding.
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The teaching, suggestion, or motivation in the prior art (i.e. WO ‘982 teaches lutetium-177-bound chelating agents can be used to create advantageous radiolabeled antibodies as they produce less damage to normal tissues, making them suitable for both therapeutics and labeling; US ‘976 teaches the IgG-binding peptide is an easy and quick way to attach a compound in a site-specific manner to an antibody) would have led one of ordinary skill to modify the prior art reference (i.e. a radiolabeled mucin subtype antibody as taught by Pat. ‘701 modified with a lutetium-177-bound chelating agent and IgG-binding peptide as taught in WO ‘105, WO ‘982, and US ‘976) to arrive at the claimed invention.
There is a reasonable expectation of success as the radionuclide lutetium-177 bound to a chelating agent and IgG-binding peptides were known modifications to antibodies, applicable to anti-mucin subtype 5AC, and used prior to the effective filing date of the application. US ‘976 expressly identifies their IgG-binding peptides can be used in conjunction with radiolabeled chelating agents and antibodies. WO ‘105 expressly identifies its mucin subtype 5AC antibody can be modified with radioisotopes. Lutetium-177 and Zr-89 are routinely used in radiolabeling as they are both radioisotopes. In addition, both WO ‘105, WO ‘982, and US ‘976 are in analogous arts (i.e. radiolabeled antibodies).
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to use a lutetium-177-bound chelating agent and IgG-binding peptide (containing the crosslinking agent) as taught in WO ‘105, WO ‘982, and US ‘976 in a radiolabeled mucin subtype antibody as taught by Pat. ‘701 to produce a more advantageous conjugate that is less likely to pose harm in a patient and wherein the IgG-binding peptide is added specifically to not interfere with antigen binding.
Claims 1-5 and 7-11 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 12569578 (hereinafter referred to as Pat. ‘578) in view of WO2013157105A1 (published 2013-10-24, hereinafter referred to as WO ‘105; IDS filed 2024-03-11, Cite No. 15) and WO2019125982A1 (published 2019-06-27, hereinafter referred to as WO ‘982).
WO ‘105 and WO ‘982 are as discussed above and incorporated by reference herein.
Instant claims 1, 4-5, 7-8, and 11 are rendered obvious by the combined teachings of the prior art as fully described in the 103 rejection section, the 103s being incorporated here. The addition of the patented claims over above over related subject matter only further supported this obviousness.
The instant claims teach a conjugate comprising an antibody, chelating agent, peptide linker, and a radionuclide that emits beta rays. Instant claim 1 teaches a conjugate comprising a radionuclide that emits beta rays and an anti-MUC5AC antibody with the VH and the VL having at least 95% sequence identity to instant SEQ ID NOs: 1-8. Instant claims 2-3 teaches VH and the VL comprising instant SEQ ID NOs: 1-8. Instant claims 4 and 7 teach various radionuclides. Instant claim 5 teaches a chelating agent comprising a chelate linker and chelate site. Instant claim 8 teaches the number of chelating agents per antibody. Instant claim 9 teaches the chelating agent modifies the Fc region of the antibody via a peptide linker. Instant claim 10 teaches a crosslinking agent and various peptide linkers. Instant claim 11 teaches various chelate sites.
The claims of Pat. ‘578 teach a conjugate comprising an antibody, chelating agent, peptide linker, and a radionuclide the emits alpha particles. Claims 1-2, 7-8, and 14 of Pat. ‘578 teach a humanized antibody specifically that binds to mucin subtype 5AC (MUC5AC) comprising SEQ ID NOs: 1-4 and SEQ ID NOs: 5-8 for the heavy and light chain variable regions respectively. SEQ ID NOs: 1-8 of Pat. ‘578 are identical to instant SEQ ID NOs: 1-8 respectively as recited in instant claims 1-3. Claim 1 of Pat. ‘578 teaches a chelating agent comprising a chelate linker and chelate site as recited in instant claim 5 and the chelating agent modifies the Fc region of the antibody via a peptide linker as recited in instant claim 9. Claim 1 of Pat. ‘578 further teaches the crosslinking agent and the identical peptide formula as recited in instant claim 10. Claim 1 of Pat. ‘578 further teaches particular chelate site structures that are species of the genus of chelate sites recited in instant claim 11. Claims 3-4 and 15-16 of Pat. ‘578 teach particular peptide linker sequences that are species of the genus of peptide linkers recited in instant claim 10. Claims 11-12 of Pat. ‘578 teach various radionuclides that emit alpha particles.
Claims 1-16 of Pat. ‘578 do not teach a radionuclide that emits beta rays (instant claim 1), specifically lutetium-177 (instant claims 4 and 7), nor the number of chelating agents per antibody (instant claim 8). These deficiencies are remedied by WO ‘105 and WO ‘982.
The radionuclide lutetium-177 bound to a chelating agent was a known modification to antibodies, applicable to anti-mucin subtype 5AC, and used prior to the effective filing date of the application. In addition, WO ‘105, WO ‘982, and Pat. ‘701 are in analogous arts (i.e. radiolabeled antibodies). Since WO ‘982 teaches lutetium-177-bound chelating agents can be used to create advantageous radiolabeled antibodies as they produce less damage to normal tissues, making them suitable for both therapeutics and labeling, there is motivation for using a lutetium-177-bound chelating agent as taught in WO ‘105 and WO ‘982 in a radiolabeled mucin subtype antibody as taught by Pat. ‘701 in order to produce a more advantageous conjugate that is less likely to pose harm in a patient.
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The teaching, suggestion, or motivation in the prior art (i.e. WO ‘982 teaches lutetium-177-bound chelating agents can be used to create advantageous radiolabeled antibodies as they produce less damage to normal tissues, making them suitable for both therapeutics and labeling) would have led one of ordinary skill to modify the prior art reference (i.e. a radiolabeled mucin subtype antibody as taught by Pat. ‘701 modified with a lutetium-177-bound chelating agent as taught in WO ‘105 and WO ‘982) to arrive at the claimed invention.
There is a reasonable expectation of success as the radionuclide lutetium-177 bound to a chelating agent was a known modification to antibodies, applicable to anti-mucin subtype 5AC, and used prior to the effective filing date of the application. WO ‘105 expressly identifies its mucin subtype 5AC antibody can be modified with radioisotopes, applicable to lutetium-177, indicating the modification would be successful. In addition, WO ‘105, WO ‘982, and Pat. ‘701 are in analogous arts (i.e. radiolabeled antibodies).
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to use a lutetium-177-bound chelating agent as taught in WO ‘105 and WO ‘982 in a radiolabeled mucin subtype antibody as taught by Pat. ‘701 to produce a more advantageous conjugate that is less likely to pose harm in a patient.
Art-Free Subject Matter
Applicant elected SEQ ID NOs: 1 and 7 for the heavy and light chain variable regions respectively for the antibody species (see Election/Restriction section for more information), applicable to instant claims 1-3. All species of instant claims 1-3 were searched, not just the elected species, as the elected species did not have prior art.
Amino acid sequences having at least 95% sequence identity to SEQ ID NOs: 1 and 8 were taught by WO2013157105A1 (published 2013-10-24, hereinafter referred to as WO ‘105; IDS filed 2024-03-11, Cite No. 15) as fully described in the 103 rejection section.
The amino acid sequences having at least 95% sequence identity to SEQ ID NOs: 5-7 and amino acid sequences have 100% sequence identity to SEQ ID NOs: 1-8 were thoroughly searched corresponding to the limitations of the claims and are free of prior art.
Conclusion
Claims 13-16 are cancelled. Claims 1-12 and 17-20 are pending. Claims 6, 12, and 17-20 are withdrawn. Claims 5 and 9-11 are objected to. Claims 1-5 and 7-11 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jessica M Priest whose telephone number is (571)272-8469. The examiner can normally be reached Mon-Fri 8am-5pm.
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, Samira Jean-Louis can be reached at (571) 270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/J.M.P./Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
