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 . 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.
Election/Restrictions
Applicant’s election without traverse of group I (peptides) and the conjugate ZD2-HZ-JAAP in the reply filed on 10 Aug, 2026 is acknowledged.
Applicants elected the structure
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169
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. A search was conducted for this compound, and references rendering it obvious were found. As a result, claim 9 was examined and claims 1-8 and 10-21 were withdrawn from consideration.
Claims Status
Claims 1-21 are pending.
Claims 1-8 and 10-21 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species or invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10 Aug, 2026.
Specification
The disclosure is objected to because of the following informalities: there are numerous synthesis schemes in the disclosure, such as at paragraph 80, paragraph 87, paragraph 90, paragraph 93, and others. Unfortunately, these are all of such poor resolution to be indecipherable.
In addition, there are sequences listed without their appropriate SEQ ID number, note paragraph 7, for example. It is also presumed that the various synthesis schemes show peptides; this rule applies to both drawings with sequences and sequences described by their 1 or 3 letter codes. The MPEP states that "37 CFR 1.821(d) requires the use of the assigned sequence identifier in all instances where the description or claims of a patent application discuss sequences regardless of whether a given sequence is also embedded in the text of the description or claims of an application” (MPEP 2422.03).
Appropriate correction is required.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 9 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. The constructs of claim 9 all use the peptide ZD2, which is defined as TVRTSAD (paragraph 7). However, this sequence comprises none of the sequences required by claim 1, making claim 9 broader than the claim it is dependent on in this respect. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
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.
Claim(s) 9 is rejected under 35 U.S.C. 103 as being unpatentable over Lu et al (US 20170224848) in view of Wang et al (Int. J. Cancer) (2021) 148(2) p437-447, available 19 July, 2020), Gayraud et al (Molecules (March, 2021) 26:1591) and Leamon et al (Bioconjugate Chem. (2006) 17 p1226-1232).
Lu et al discusses targeting peptides (title) that bind to cancer (paragraph 4), including SEQ ID 1 (paragraph 5), identical with ZD2 of the examined claims. These can be conjugated to a therapeutic agent and administered to a patient for treating cancer (paragraph 101). There can be a linker between the peptide and the therapeutic agent (paragraphs 52 and 56).
The difference between this reference and the examined claims is that this reference does not specify the same therapeutic agent/linkers as claimed by applicants.
Wang et al discuss a conjugate of JQ-1 for treating cancer (title). JQ-1 induces apoptosis and autophagy of cancer cells and reduces the ability of tumors to evade the immune system (p437, 2nd column, 1st paragraph, continues to p438, 1st column, 1st paragraph). However, there are toxicity issues with JQ-1; conjugation with other agents is explored as a way to overcome this limitation (p438, 1st column, 1st paragraph). Conjugation was through the carboxylate of JQ-1 carboxylate to form an amide (Sup. Fig 1, 13th page). This reference discusses JQ-1 as an anti-cancer therapeutic and demonstrates conjugation of the molecule.
Gayraud et al discuss conjugation to peptides (title). Succinic acid is a commonly used bifunctional liker, which is connected to the peptide via an amide bond, while the other side has a labile link (9th page, 6th paragraph, continues to 10th page, 1st paragraph). Examples are given of attaching the linker to the N-terminus of a peptide and connecting the other side to an anticancer agent, which increased the potency of the material (10th page, 2nd paragraph). This is a user friendly tool to attach a drug to a peptide with a straightforward synthesis route (10th page, 3d paragraph). Note that the chemistry used for the labile link requires a hydroxyl group on the drug, a feature that JQ-1 does not have. This reference discusses using a succinic acid linker to connect a peptide to a drug.
Leaman et al states that the toxicity of a chemotherapeutic can be lowered by specifically targeting it to cancer cells (p1226, 1st column, 2nd paragraph). The reference uses a folate to target agents (p1226, 1st column, 3d paragraph), and are using it to direct a vinca alkaloid to cancer cells (p1226, 2nd column, 1st paragraph). The design is a targeting agent, attached to a spacer, which is linked to a cleavable bond, which connects to the drug moiety (fig 1a, p1228, top of page). The authors used an acyl hydrazone bond, which releases the drug in an acid milieu (p1231, 1st column, 2nd paragraph). The specific acyl hydrazone bond was formed by reacting a p-modified acetophenone with a hydrazine derivative (scheme 1, p1229, top of page). While the activity in vitro was almost equivalent to the vinca alkaloid alone (fig 3, p1229, 2nd column, bottom of page), the conjugate proved to have better activity in vivo (p1230, 1st column, 1st paragraph) and a much better toxicity profile (table 1, p1230, bottom of page). This reference discusses an acetophenone hydrazone as an acid labile linker.
Therefore, it would be obvious to use the JQ-1 as the targeting agent in the construct of Lu et al, as a substitution of one known element (the JQ-1 of Wang et al) for another (the therapeutic agent of Lu et al) yielding expected results (targeted anti-cancer agent). As this is the same approach that Leamon et al states will reduce the off target toxicity of a chemotherapeutic drug, an artisan in this field would attempt this substitution with a reasonable expectation of success.
Furthermore, it would be obvious to use a succinic acid linker to connect the peptide of Lu et al and the drug of Wang et al, as Gayraud et al teaches it is a simple, user friendly way to connect an anti-cancer drug to a peptide. As the reference states that this is a common linker, an artisan in this field would be expected to have some familiarity with it, leading to a reasonable expectation of success.
Finally, it would be obvious to add the acetophenone hydrazone of Leamon et al, to allow for cleavage in an acidic environment. Alternatively, this is a substitution of the cleavable linker of Gayraud et al for the cleavable linker of Leamon et al, yielding expected results of a cleavable66 linker. As Leamon et al shows that targeting a drug can improve it’s toxicity profile, an artisan in this field would attempt this substitution with a reasonable expectation of success.
Lu et al discusses a cancer therapeutic using the sequence ZD2 attached to a therapeutic, and suggests a linker. Wang et al suggests using JQ-1 as the therapeutic, linked via a carboxylate to form an amide. GAyraud et al and Leamon et al together render obvious an acetophenone hydrazone attached to a succinic acid as a linker. Note that this construct is ZD2-HZ-JAAP, applicant’s elected construct, rendering obvious claim 9.
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.
first rejection
Claim 9 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 6 of copending Application No. 19/568,231 in view of Leamon et al (Bioconjugate Chem. (2006) 17 p1226-1232), Wang et al (Int. J. Cancer) (2021) 148(2) p437-447, available 19 July, 2020), and Gayraud et al (Molecules (March, 2021) 26:1591).
Competing claim 6 describes a method of detecting cancer, comprising administering a construct with a peptide P, selected from a Markush group including SEQ ID 1, identical to ZD2 of the examined claims, attached to a PET/SPECT agent via an optional linker.
The difference between the competing claims and the examined claim is that the competing claim does not define the linker, and uses a different agent.
Leaman et al states that the toxicity of a chemotherapeutic can be lowered by specifically targeting it to cancer cells (p1226, 1st column, 2nd paragraph). The reference uses a folate to target agents (p1226, 1st column, 3d paragraph), and are using it to direct a vinca alkaloid to cancer cells (p1226, 2nd column, 1st paragraph). The design is a targeting agent, attached to a spacer, which is linked to a cleavable bond, which connects to the drug moiety (fig 1a, p1228, top of page). The authors used an acyl hydrazone bond, which releases the drug in an acid milieu (p1231, 1st column, 2nd paragraph). The specific acyl hydrazone bond was formed by reacting a p-modified acetophenone with a hydrazine derivative (scheme 1, p1229, top of page). While the activity in vitro was almost equivalent to the vinca alkaloid alone (fig 3, p1229, 2nd column, bottom of page), the conjugate proved to have better activity in vivo (p1230, 1st column, 1st paragraph) and a much better toxicity profile (table 1, p1230, bottom of page). This reference discusses an acetophenone hydrazone as an acid labile linker.
Wang et al discuss a conjugate of JQ-1 for treating cancer (title). JQ-1 induces apoptosis and autophagy of cancer cells and reduces the ability of tumors to evade the immune system (p437, 2nd column, 1st paragraph, continues to p438, 1st column, 1st paragraph). However, there are toxicity issues with JQ-1; conjugation with other agents is explored as a way to overcome this limitation (p438, 1st column, 1st paragraph). Conjugation was through the carboxylate of JQ-1 carboxylate to form an amide (Sup. Fig 1, 13th page). This reference discusses JQ-1 as an anti-cancer therapeutic and demonstrates conjugation of the molecule.
Gayraud et al discuss conjugation to peptides (title). Succinic acid is a commonly used bifunctional liker, which is connected to the peptide via an amide bond, while the other side has a labile link (9th page, 6th paragraph, continues to 10th page, 1st paragraph). Examples are given of attaching the linker to the N-terminus of a peptide and connecting the other side to an anticancer agent, which increased the potency of the material (10th page, 2nd paragraph). This is a user friendly tool to attach a drug to a peptide with a straightforward synthesis route (10th page, 3d paragraph). Note that the chemistry used for the labile link requires a hydroxyl group on the drug, a feature that JQ-1 does not have. This reference discusses using a succinic acid linker to connect a peptide to a drug.
Therefore, it would be obvious to substitute the detectable moiety of the competing claims with the therapeutic JQ-1, as Leamon et al states that this will reduce the toxicity of this species noted by Wang et al. As this is a common approach to this issue, an artisan in this field would attempt this modification with a reasonable expectation of success.
Furthermore, it would be obvious to use a succinic acid linker as a substitution of one known element (the succinic acid linker of Gayraud et al) for another (the unspecified linker of the competing claims) yielding expected results (connection of the components of the construct). As this is a very common linker, an artisan in this field would attempt this modification with a reasonable expectation of success.
Finally, it would be obvious to add the acetophenone hydrazone of Leamon et al, to allow for cleavage in an acidic environment. Alternatively, this is a substitution of the cleavable linker of Gayraud et al for the cleavable linker of Leamon et al, yielding expected results of an acid labile linker. As Leamon et al shows that targeting a drug can improve it’s toxicity profile, an artisan in this field would attempt this substitution with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
second rejection
Claim 9 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 5 of U.S. Patent No. 12,576,168 in view of Leamon et al (Bioconjugate Chem. (2006) 17 p1226-1232), Wang et al (Int. J. Cancer) (2021) 148(2) p437-447, available 19 July, 2020), and Gayraud et al (Molecules (March, 2021) 26:1591).
Competing claim 5 describes a method of detecting cancer, comprising administering a construct with a peptide P, selected from a Markush group including SEQ ID 1, identical to ZD2 of the examined claims, attached to a PET/SPECT agent via an optional linker.
The difference between the competing claims and the examined claim is that the competing claim does not define the linker, and uses a different agent.
Leaman et al states that the toxicity of a chemotherapeutic can be lowered by specifically targeting it to cancer cells (p1226, 1st column, 2nd paragraph). The reference uses a folate to target agents (p1226, 1st column, 3d paragraph), and are using it to direct a vinca alkaloid to cancer cells (p1226, 2nd column, 1st paragraph). The design is a targeting agent, attached to a spacer, which is linked to a cleavable bond, which connects to the drug moiety (fig 1a, p1228, top of page). The authors used an acyl hydrazone bond, which releases the drug in an acid milieu (p1231, 1st column, 2nd paragraph). The specific acyl hydrazone bond was formed by reacting a p-modified acetophenone with a hydrazine derivative (scheme 1, p1229, top of page). While the activity in vitro was almost equivalent to the vinca alkaloid alone (fig 3, p1229, 2nd column, bottom of page), the conjugate proved to have better activity in vivo (p1230, 1st column, 1st paragraph) and a much better toxicity profile (table 1, p1230, bottom of page). This reference discusses an acetophenone hydrazone as an acid labile linker.
Wang et al discuss a conjugate of JQ-1 for treating cancer (title). JQ-1 induces apoptosis and autophagy of cancer cells and reduces the ability of tumors to evade the immune system (p437, 2nd column, 1st paragraph, continues to p438, 1st column, 1st paragraph). However, there are toxicity issues with JQ-1; conjugation with other agents is explored as a way to overcome this limitation (p438, 1st column, 1st paragraph). Conjugation was through the carboxylate of JQ-1 carboxylate to form an amide (Sup. Fig 1, 13th page). This reference discusses JQ-1 as an anti-cancer therapeutic and demonstrates conjugation of the molecule.
Gayraud et al discuss conjugation to peptides (title). Succinic acid is a commonly used bifunctional liker, which is connected to the peptide via an amide bond, while the other side has a labile link (9th page, 6th paragraph, continues to 10th page, 1st paragraph). Examples are given of attaching the linker to the N-terminus of a peptide and connecting the other side to an anticancer agent, which increased the potency of the material (10th page, 2nd paragraph). This is a user friendly tool to attach a drug to a peptide with a straightforward synthesis route (10th page, 3d paragraph). Note that the chemistry used for the labile link requires a hydroxyl group on the drug, a feature that JQ-1 does not have. This reference discusses using a succinic acid linker to connect a peptide to a drug.
Therefore, it would be obvious to substitute the detectable moiety of the competing claims with the therapeutic JQ-1, as Leamon et al states that this will reduce the toxicity of this species noted by Wang et al. As this is a common approach to this issue, an artisan in this field would attempt this modification with a reasonable expectation of success.
Furthermore, it would be obvious to use a succinic acid linker as a substitution of one known element (the succinic acid linker of Gayraud et al) for another (the unspecified linker of the competing claims) yielding expected results (connection of the components of the construct). As this is a very common linker, an artisan in this field would attempt this modification with a reasonable expectation of success.
Finally, it would be obvious to add the acetophenone hydrazone of Leamon et al, to allow for cleavage in an acidic environment. Alternatively, this is a substitution of the cleavable linker of Gayraud et al for the cleavable linker of Leamon et al, yielding expected results of an acid labile linker. As Leamon et al shows that targeting a drug can improve it’s toxicity profile, an artisan in this field would attempt this substitution with a reasonable expectation of success.
third rejection
Claim 9 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 14 of copending Application No. 18/625,695 (US 20240325574) in view of Leamon et al (Bioconjugate Chem. (2006) 17 p1226-1232), Wang et al (Int. J. Cancer) (2021) 148(2) p437-447, available 19 July, 2020), and Gayraud et al (Molecules (March, 2021) 26:1591).
Competing claim 14 describes a method of detecting cancer, comprising administering a construct with a peptide P, selected from a Markush group including SEQ ID 1, identical to ZD2 of the examined claims, attached to an imaging agent via an optional linker.
The difference between the competing claims and the examined claim is that the competing claim does not define the linker, and uses a different agent.
Leaman et al states that the toxicity of a chemotherapeutic can be lowered by specifically targeting it to cancer cells (p1226, 1st column, 2nd paragraph). The reference uses a folate to target agents (p1226, 1st column, 3d paragraph), and are using it to direct a vinca alkaloid to cancer cells (p1226, 2nd column, 1st paragraph). The design is a targeting agent, attached to a spacer, which is linked to a cleavable bond, which connects to the drug moiety (fig 1a, p1228, top of page). The authors used an acyl hydrazone bond, which releases the drug in an acid milieu (p1231, 1st column, 2nd paragraph). The specific acyl hydrazone bond was formed by reacting a p-modified acetophenone with a hydrazine derivative (scheme 1, p1229, top of page). While the activity in vitro was almost equivalent to the vinca alkaloid alone (fig 3, p1229, 2nd column, bottom of page), the conjugate proved to have better activity in vivo (p1230, 1st column, 1st paragraph) and a much better toxicity profile (table 1, p1230, bottom of page). This reference discusses an acetophenone hydrazone as an acid labile linker.
Wang et al discuss a conjugate of JQ-1 for treating cancer (title). JQ-1 induces apoptosis and autophagy of cancer cells and reduces the ability of tumors to evade the immune system (p437, 2nd column, 1st paragraph, continues to p438, 1st column, 1st paragraph). However, there are toxicity issues with JQ-1; conjugation with other agents is explored as a way to overcome this limitation (p438, 1st column, 1st paragraph). Conjugation was through the carboxylate of JQ-1 carboxylate to form an amide (Sup. Fig 1, 13th page). This reference discusses JQ-1 as an anti-cancer therapeutic and demonstrates conjugation of the molecule.
Gayraud et al discuss conjugation to peptides (title). Succinic acid is a commonly used bifunctional liker, which is connected to the peptide via an amide bond, while the other side has a labile link (9th page, 6th paragraph, continues to 10th page, 1st paragraph). Examples are given of attaching the linker to the N-terminus of a peptide and connecting the other side to an anticancer agent, which increased the potency of the material (10th page, 2nd paragraph). This is a user friendly tool to attach a drug to a peptide with a straightforward synthesis route (10th page, 3d paragraph). Note that the chemistry used for the labile link requires a hydroxyl group on the drug, a feature that JQ-1 does not have. This reference discusses using a succinic acid linker to connect a peptide to a drug.
Therefore, it would be obvious to substitute the detectable moiety of the competing claims with the therapeutic JQ-1, as Leamon et al states that this will reduce the toxicity of this species noted by Wang et al. As this is a common approach to this issue, an artisan in this field would attempt this modification with a reasonable expectation of success.
Furthermore, it would be obvious to use a succinic acid linker as a substitution of one known element (the succinic acid linker of Gayraud et al) for another (the unspecified linker of the competing claims) yielding expected results (connection of the components of the construct). As this is a very common linker, an artisan in this field would attempt this modification with a reasonable expectation of success.
Finally, it would be obvious to add the acetophenone hydrazone of Leamon et al, to allow for cleavage in an acidic environment. Alternatively, this is a substitution of the cleavable linker of Gayraud et al for the cleavable linker of Leamon et al, yielding expected results of an acid labile linker. As Leamon et al shows that targeting a drug can improve it’s toxicity profile, an artisan in this field would attempt this substitution with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
fourth rejection
Claim 9 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 11, and 14 of copending Application No. 18,721,744 (US 20250057990 in view of Leamon et al (Bioconjugate Chem. (2006) 17 p1226-1232), Wang et al (Int. J. Cancer) (2021) 148(2) p437-447, available 19 July, 2020), and Gayraud et al (Molecules (March, 2021) 26:1591).
Competing claim 1 describes a construct comprising a targeting moiety attached to an MRI agent. Competing claim 11 specifies targeting a cancer antigen, making this an agent for detecting cancer. Competing claim 12 specifies that the targeting agent is selected from a Markush group including SEQ ID 1, identical to ZD2 of the examined claims, attached to a PET/SPECT agent via an optional linker.
The difference between the competing claims and the examined claim is that the competing claim does not define the linker, and uses a different agent.
Leaman et al states that the toxicity of a chemotherapeutic can be lowered by specifically targeting it to cancer cells (p1226, 1st column, 2nd paragraph). The reference uses a folate to target agents (p1226, 1st column, 3d paragraph), and are using it to direct a vinca alkaloid to cancer cells (p1226, 2nd column, 1st paragraph). The design is a targeting agent, attached to a spacer, which is linked to a cleavable bond, which connects to the drug moiety (fig 1a, p1228, top of page). The authors used an acyl hydrazone bond, which releases the drug in an acid milieu (p1231, 1st column, 2nd paragraph). The specific acyl hydrazone bond was formed by reacting a p-modified acetophenone with a hydrazine derivative (scheme 1, p1229, top of page). While the activity in vitro was almost equivalent to the vinca alkaloid alone (fig 3, p1229, 2nd column, bottom of page), the conjugate proved to have better activity in vivo (p1230, 1st column, 1st paragraph) and a much better toxicity profile (table 1, p1230, bottom of page). This reference discusses an acetophenone hydrazone as an acid labile linker.
Wang et al discuss a conjugate of JQ-1 for treating cancer (title). JQ-1 induces apoptosis and autophagy of cancer cells and reduces the ability of tumors to evade the immune system (p437, 2nd column, 1st paragraph, continues to p438, 1st column, 1st paragraph). However, there are toxicity issues with JQ-1; conjugation with other agents is explored as a way to overcome this limitation (p438, 1st column, 1st paragraph). Conjugation was through the carboxylate of JQ-1 carboxylate to form an amide (Sup. Fig 1, 13th page). This reference discusses JQ-1 as an anti-cancer therapeutic and demonstrates conjugation of the molecule.
Gayraud et al discuss conjugation to peptides (title). Succinic acid is a commonly used bifunctional liker, which is connected to the peptide via an amide bond, while the other side has a labile link (9th page, 6th paragraph, continues to 10th page, 1st paragraph). Examples are given of attaching the linker to the N-terminus of a peptide and connecting the other side to an anticancer agent, which increased the potency of the material (10th page, 2nd paragraph). This is a user friendly tool to attach a drug to a peptide with a straightforward synthesis route (10th page, 3d paragraph). Note that the chemistry used for the labile link requires a hydroxyl group on the drug, a feature that JQ-1 does not have. This reference discusses using a succinic acid linker to connect a peptide to a drug.
Therefore, it would be obvious to substitute the detectable moiety of the competing claims with the therapeutic JQ-1, as Leamon et al states that this will reduce the toxicity of this species noted by Wang et al. As this is a common approach to this issue, an artisan in this field would attempt this modification with a reasonable expectation of success.
Furthermore, it would be obvious to use a succinic acid linker as a substitution of one known element (the succinic acid linker of Gayraud et al) for another (the unspecified linker of the competing claims) yielding expected results (connection of the components of the construct). As this is a very common linker, an artisan in this field would attempt this modification with a reasonable expectation of success.
Finally, it would be obvious to add the acetophenone hydrazone of Leamon et al, to allow for cleavage in an acidic environment. Alternatively, this is a substitution of the cleavable linker of Gayraud et al for the cleavable linker of Leamon et al, yielding expected results of an acid labile linker. As Leamon et al shows that targeting a drug can improve it’s toxicity profile, an artisan in this field would attempt this substitution with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
fifth rejection
Claim 9 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10,124,073 in view of Leamon et al (Bioconjugate Chem. (2006) 17 p1226-1232), Wang et al (Int. J. Cancer) (2021) 148(2) p437-447, available 19 July, 2020), and Gayraud et al (Molecules (March, 2021) 26:1591).
Competing claim 1 describes a construct for detecting cancer, comprising a peptide P, selected from a Markush group including SEQ ID 1, identical to ZD2 of the examined claims, attached to a detectable moiety.
The difference between the competing claims and the examined claim is that the competing claim does not define the linker, and uses a different agent.
Leaman et al states that the toxicity of a chemotherapeutic can be lowered by specifically targeting it to cancer cells (p1226, 1st column, 2nd paragraph). The reference uses a folate to target agents (p1226, 1st column, 3d paragraph), and are using it to direct a vinca alkaloid to cancer cells (p1226, 2nd column, 1st paragraph). The design is a targeting agent, attached to a spacer, which is linked to a cleavable bond, which connects to the drug moiety (fig 1a, p1228, top of page). The authors used an acyl hydrazone bond, which releases the drug in an acid milieu (p1231, 1st column, 2nd paragraph). The specific acyl hydrazone bond was formed by reacting a p-modified acetophenone with a hydrazine derivative (scheme 1, p1229, top of page). While the activity in vitro was almost equivalent to the vinca alkaloid alone (fig 3, p1229, 2nd column, bottom of page), the conjugate proved to have better activity in vivo (p1230, 1st column, 1st paragraph) and a much better toxicity profile (table 1, p1230, bottom of page). This reference discusses an acetophenone hydrazone as an acid labile linker.
Wang et al discuss a conjugate of JQ-1 for treating cancer (title). JQ-1 induces apoptosis and autophagy of cancer cells and reduces the ability of tumors to evade the immune system (p437, 2nd column, 1st paragraph, continues to p438, 1st column, 1st paragraph). However, there are toxicity issues with JQ-1; conjugation with other agents is explored as a way to overcome this limitation (p438, 1st column, 1st paragraph). Conjugation was through the carboxylate of JQ-1 carboxylate to form an amide (Sup. Fig 1, 13th page). This reference discusses JQ-1 as an anti-cancer therapeutic and demonstrates conjugation of the molecule.
Gayraud et al discuss conjugation to peptides (title). Succinic acid is a commonly used bifunctional liker, which is connected to the peptide via an amide bond, while the other side has a labile link (9th page, 6th paragraph, continues to 10th page, 1st paragraph). Examples are given of attaching the linker to the N-terminus of a peptide and connecting the other side to an anticancer agent, which increased the potency of the material (10th page, 2nd paragraph). This is a user friendly tool to attach a drug to a peptide with a straightforward synthesis route (10th page, 3d paragraph). Note that the chemistry used for the labile link requires a hydroxyl group on the drug, a feature that JQ-1 does not have. This reference discusses using a succinic acid linker to connect a peptide to a drug.
Therefore, it would be obvious to substitute the detectable moiety of the competing claims with the therapeutic JQ-1, as Leamon et al states that this will reduce the toxicity of this species noted by Wang et al. As this is a common approach to this issue, an artisan in this field would attempt this modification with a reasonable expectation of success.
Furthermore, it would be obvious to use a succinic acid linker as a substitution of one known element (the succinic acid linker of Gayraud et al) for another (the unspecified linker of the competing claims) yielding expected results (connection of the components of the construct). As this is a very common linker, an artisan in this field would attempt this modification with a reasonable expectation of success.
Finally, it would be obvious to add the acetophenone hydrazone of Leamon et al, to allow for cleavage in an acidic environment. Alternatively, this is a substitution of the cleavable linker of Gayraud et al for the cleavable linker of Leamon et al, yielding expected results of an acid labile linker. As Leamon et al shows that targeting a drug can improve it’s toxicity profile, an artisan in this field would attempt this substitution with a reasonable expectation of success.
sixth rejection
Claim 9 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10,925,980 in view of Leamon et al (Bioconjugate Chem. (2006) 17 p1226-1232), Wang et al (Int. J. Cancer) (2021) 148(2) p437-447, available 19 July, 2020), and Gayraud et al (Molecules (March, 2021) 26:1591).
Competing claim 1 describes a construct for detecting cancer, comprising a peptide selected from a Markush group including SEQ ID 1, identical to ZD2 of the examined claims, attached to a detectable moiety.
The difference between the competing claims and the examined claim is that the competing claim does not define the linker, and uses a different agent.
Leaman et al states that the toxicity of a chemotherapeutic can be lowered by specifically targeting it to cancer cells (p1226, 1st column, 2nd paragraph). The reference uses a folate to target agents (p1226, 1st column, 3d paragraph), and are using it to direct a vinca alkaloid to cancer cells (p1226, 2nd column, 1st paragraph). The design is a targeting agent, attached to a spacer, which is linked to a cleavable bond, which connects to the drug moiety (fig 1a, p1228, top of page). The authors used an acyl hydrazone bond, which releases the drug in an acid milieu (p1231, 1st column, 2nd paragraph). The specific acyl hydrazone bond was formed by reacting a p-modified acetophenone with a hydrazine derivative (scheme 1, p1229, top of page). While the activity in vitro was almost equivalent to the vinca alkaloid alone (fig 3, p1229, 2nd column, bottom of page), the conjugate proved to have better activity in vivo (p1230, 1st column, 1st paragraph) and a much better toxicity profile (table 1, p1230, bottom of page). This reference discusses an acetophenone hydrazone as an acid labile linker.
Wang et al discuss a conjugate of JQ-1 for treating cancer (title). JQ-1 induces apoptosis and autophagy of cancer cells and reduces the ability of tumors to evade the immune system (p437, 2nd column, 1st paragraph, continues to p438, 1st column, 1st paragraph). However, there are toxicity issues with JQ-1; conjugation with other agents is explored as a way to overcome this limitation (p438, 1st column, 1st paragraph). Conjugation was through the carboxylate of JQ-1 carboxylate to form an amide (Sup. Fig 1, 13th page). This reference discusses JQ-1 as an anti-cancer therapeutic and demonstrates conjugation of the molecule.
Gayraud et al discuss conjugation to peptides (title). Succinic acid is a commonly used bifunctional liker, which is connected to the peptide via an amide bond, while the other side has a labile link (9th page, 6th paragraph, continues to 10th page, 1st paragraph). Examples are given of attaching the linker to the N-terminus of a peptide and connecting the other side to an anticancer agent, which increased the potency of the material (10th page, 2nd paragraph). This is a user friendly tool to attach a drug to a peptide with a straightforward synthesis route (10th page, 3d paragraph). Note that the chemistry used for the labile link requires a hydroxyl group on the drug, a feature that JQ-1 does not have. This reference discusses using a succinic acid linker to connect a peptide to a drug.
Therefore, it would be obvious to substitute the detectable moiety of the competing claims with the therapeutic JQ-1, as Leamon et al states that this will reduce the toxicity of this species noted by Wang et al. As this is a common approach to this issue, an artisan in this field would attempt this modification with a reasonable expectation of success.
Furthermore, it would be obvious to use a succinic acid linker as a substitution of one known element (the succinic acid linker of Gayraud et al) for another (the unspecified linker of the competing claims) yielding expected results (connection of the components of the construct). As this is a very common linker, an artisan in this field would attempt this modification with a reasonable expectation of success.
Finally, it would be obvious to add the acetophenone hydrazone of Leamon et al, to allow for cleavage in an acidic environment. Alternatively, this is a substitution of the cleavable linker of Gayraud et al for the cleavable linker of Leamon et al, yielding expected results of an acid labile linker. As Leamon et al shows that targeting a drug can improve it’s toxicity profile, an artisan in this field would attempt this substitution with a reasonable expectation of success.
eighth rejection
Claim 9 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11.738,099 in view of Leamon et al (Bioconjugate Chem. (2006) 17 p1226-1232), Wang et al (Int. J. Cancer) (2021) 148(2) p437-447, available 19 July, 2020), and Gayraud et al (Molecules (March, 2021) 26:1591).
Competing claim 1 describes a construct, comprising a peptide selected from a Markush group including SEQ ID 1, identical to ZD2 of the examined claims, attached to a detectable moiety.
The difference between the competing claims and the examined claim is that the competing claim does not define the linker, and uses a different agent.
Leaman et al states that the toxicity of a chemotherapeutic can be lowered by specifically targeting it to cancer cells (p1226, 1st column, 2nd paragraph). The reference uses a folate to target agents (p1226, 1st column, 3d paragraph), and are using it to direct a vinca alkaloid to cancer cells (p1226, 2nd column, 1st paragraph). The design is a targeting agent, attached to a spacer, which is linked to a cleavable bond, which connects to the drug moiety (fig 1a, p1228, top of page). The authors used an acyl hydrazone bond, which releases the drug in an acid milieu (p1231, 1st column, 2nd paragraph). The specific acyl hydrazone bond was formed by reacting a p-modified acetophenone with a hydrazine derivative (scheme 1, p1229, top of page). While the activity in vitro was almost equivalent to the vinca alkaloid alone (fig 3, p1229, 2nd column, bottom of page), the conjugate proved to have better activity in vivo (p1230, 1st column, 1st paragraph) and a much better toxicity profile (table 1, p1230, bottom of page). This reference discusses an acetophenone hydrazone as an acid labile linker.
Wang et al discuss a conjugate of JQ-1 for treating cancer (title). JQ-1 induces apoptosis and autophagy of cancer cells and reduces the ability of tumors to evade the immune system (p437, 2nd column, 1st paragraph, continues to p438, 1st column, 1st paragraph). However, there are toxicity issues with JQ-1; conjugation with other agents is explored as a way to overcome this limitation (p438, 1st column, 1st paragraph). Conjugation was through the carboxylate of JQ-1 carboxylate to form an amide (Sup. Fig 1, 13th page). This reference discusses JQ-1 as an anti-cancer therapeutic and demonstrates conjugation of the molecule.
Gayraud et al discuss conjugation to peptides (title). Succinic acid is a commonly used bifunctional liker, which is connected to the peptide via an amide bond, while the other side has a labile link (9th page, 6th paragraph, continues to 10th page, 1st paragraph). Examples are given of attaching the linker to the N-terminus of a peptide and connecting the other side to an anticancer agent, which increased the potency of the material (10th page, 2nd paragraph). This is a user friendly tool to attach a drug to a peptide with a straightforward synthesis route (10th page, 3d paragraph). Note that the chemistry used for the labile link requires a hydroxyl group on the drug, a feature that JQ-1 does not have. This reference discusses using a succinic acid linker to connect a peptide to a drug.
Therefore, it would be obvious to substitute the detectable moiety of the competing claims with the therapeutic JQ-1, as Leamon et al states that this will reduce the toxicity of this species noted by Wang et al. As this is a common approach to this issue, an artisan in this field would attempt this modification with a reasonable expectation of success.
Furthermore, it would be obvious to use a succinic acid linker as a substitution of one known element (the succinic acid linker of Gayraud et al) for another (the unspecified linker of the competing claims) yielding expected results (connection of the components of the construct). As this is a very common linker, an artisan in this field would attempt this modification with a reasonable expectation of success.
Finally, it would be obvious to add the acetophenone hydrazone of Leamon et al, to allow for cleavage in an acidic environment. Alternatively, this is a substitution of the cleavable linker of Gayraud et al for the cleavable linker of Leamon et al, yielding expected results of an acid labile linker. As Leamon et al shows that targeting a drug can improve it’s toxicity profile, an artisan in this field would attempt this substitution with a reasonable expectation of success.
fifth rejection
Claim 9 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10,925,980 in view of Leamon et al (Bioconjugate Chem. (2006) 17 p1226-1232), Wang et al (Int. J. Cancer) (2021) 148(2) p437-447, available 19 July, 2020), and Gayraud et al (Molecules (March, 2021) 26:1591).
Competing claim 1 describes a construct for detecting cancer, comprising a peptide selected from a Markush group including SEQ ID 1, identical to ZD2 of the examined claims, attached to a detectable moiety.
The difference between the competing claims and the examined claim is that the competing claim does not define the linker, and uses a different agent.
Leaman et al states that the toxicity of a chemotherapeutic can be lowered by specifically targeting it to cancer cells (p1226, 1st column, 2nd paragraph). The reference uses a folate to target agents (p1226, 1st column, 3d paragraph), and are using it to direct a vinca alkaloid to cancer cells (p1226, 2nd column, 1st paragraph). The design is a targeting agent, attached to a spacer, which is linked to a cleavable bond, which connects to the drug moiety (fig 1a, p1228, top of page). The authors used an acyl hydrazone bond, which releases the drug in an acid milieu (p1231, 1st column, 2nd paragraph). The specific acyl hydrazone bond was formed by reacting a p-modified acetophenone with a hydrazine derivative (scheme 1, p1229, top of page). While the activity in vitro was almost equivalent to the vinca alkaloid alone (fig 3, p1229, 2nd column, bottom of page), the conjugate proved to have better activity in vivo (p1230, 1st column, 1st paragraph) and a much better toxicity profile (table 1, p1230, bottom of page). This reference discusses an acetophenone hydrazone as an acid labile linker.
Wang et al discuss a conjugate of JQ-1 for treating cancer (title). JQ-1 induces apoptosis and autophagy of cancer cells and reduces the ability of tumors to evade the immune system (p437, 2nd column, 1st paragraph, continues to p438, 1st column, 1st paragraph). However, there are toxicity issues with JQ-1; conjugation with other agents is explored as a way to overcome this limitation (p438, 1st column, 1st paragraph). Conjugation was through the carboxylate of JQ-1 carboxylate to form an amide (Sup. Fig 1, 13th page). This reference discusses JQ-1 as an anti-cancer therapeutic and demonstrates conjugation of the molecule.
Gayraud et al discuss conjugation to peptides (title). Succinic acid is a commonly used bifunctional liker, which is connected to the peptide via an amide bond, while the other side has a labile link (9th page, 6th paragraph, continues to 10th page, 1st paragraph). Examples are given of attaching the linker to the N-terminus of a peptide and connecting the other side to an anticancer agent, which increased the potency of the material (10th page, 2nd paragraph). This is a user friendly tool to attach a drug to a peptide with a straightforward synthesis route (10th page, 3d paragraph). Note that the chemistry used for the labile link requires a hydroxyl group on the drug, a feature that JQ-1 does not have. This reference discusses using a succinic acid linker to connect a peptide to a drug.
Therefore, it would be obvious to substitute the detectable moiety of the competing claims with the therapeutic JQ-1, as Leamon et al states that this will reduce the toxicity of this species noted by Wang et al. As this is a common approach to this issue, an artisan in this field would attempt this modification with a reasonable expectation of success.
Furthermore, it would be obvious to use a succinic acid linker as a substitution of one known element (the succinic acid linker of Gayraud et al) for another (the unspecified linker of the competing claims) yielding expected results (connection of the components of the construct). As this is a very common linker, an artisan in this field would attempt this modification with a reasonable expectation of success.
Finally, it would be obvious to add the acetophenone hydrazone of Leamon et al, to allow for cleavage in an acidic environment. Alternatively, this is a substitution of the cleavable linker of Gayraud et al for the cleavable linker of Leamon et al, yielding expected results of an acid labile linker. As Leamon et al shows that targeting a drug can improve it’s toxicity profile, an artisan in this field would attempt this substitution with a reasonable expectation of success.
ninth rejection
Claim 9 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 5 of U.S. Patent No. 12,599,684 in view of Leamon et al (Bioconjugate Chem. (2006) 17 p1226-1232), Wang et al (Int. J. Cancer) (2021) 148(2) p437-447, available 19 July, 2020), and Gayraud et al (Molecules (March, 2021) 26:1591).
Competing claim 5 describes a construct for detecting cancer, comprising a peptide selected from a Markush group including SEQ ID 1, identical to ZD2 of the examined claims, attached to a detectable moiety via a linker.
The difference between the competing claims and the examined claim is that the competing claim does not define the linker, and uses a different agent.
Leaman et al states that the toxicity of a chemotherapeutic can be lowered by specifically targeting it to cancer cells (p1226, 1st column, 2nd paragraph). The reference uses a folate to target agents (p1226, 1st column, 3d paragraph), and are using it to direct a vinca alkaloid to cancer cells (p1226, 2nd column, 1st paragraph). The design is a targeting agent, attached to a spacer, which is linked to a cleavable bond, which connects to the drug moiety (fig 1a, p1228, top of page). The authors used an acyl hydrazone bond, which releases the drug in an acid milieu (p1231, 1st column, 2nd paragraph). The specific acyl hydrazone bond was formed by reacting a p-modified acetophenone with a hydrazine derivative (scheme 1, p1229, top of page). While the activity in vitro was almost equivalent to the vinca alkaloid alone (fig 3, p1229, 2nd column, bottom of page), the conjugate proved to have better activity in vivo (p1230, 1st column, 1st paragraph) and a much better toxicity profile (table 1, p1230, bottom of page). This reference discusses an acetophenone hydrazone as an acid labile linker.
Wang et al discuss a conjugate of JQ-1 for treating cancer (title). JQ-1 induces apoptosis and autophagy of cancer cells and reduces the ability of tumors to evade the immune system (p437, 2nd column, 1st paragraph, continues to p438, 1st column, 1st paragraph). However, there are toxicity issues with JQ-1; conjugation with other agents is explored as a way to overcome this limitation (p438, 1st column, 1st paragraph). Conjugation was through the carboxylate of JQ-1 carboxylate to form an amide (Sup. Fig 1, 13th page). This reference discusses JQ-1 as an anti-cancer therapeutic and demonstrates conjugation of the molecule.
Gayraud et al discuss conjugation to peptides (title). Succinic acid is a commonly used bifunctional liker, which is connected to the peptide via an amide bond, while the other side has a labile link (9th page, 6th paragraph, continues to 10th page, 1st paragraph). Examples are given of attaching the linker to the N-terminus of a peptide and connecting the other side to an anticancer agent, which increased the potency of the material (10th page, 2nd paragraph). This is a user friendly tool to attach a drug to a peptide with a straightforward synthesis route (10th page, 3d paragraph). Note that the chemistry used for the labile link requires a hydroxyl group on the drug, a feature that JQ-1 does not have. This reference discusses using a succinic acid linker to connect a peptide to a drug.
Therefore, it would be obvious to substitute the detectable moiety of the competing claims with the therapeutic JQ-1, as Leamon et al states that this will reduce the toxicity of this species noted by Wang et al. As this is a common approach to this issue, an artisan in this field would attempt this modification with a reasonable expectation of success.
Furthermore, it would be obvious to use a succinic acid linker as a substitution of one known element (the succinic acid linker of Gayraud et al) for another (the unspecified linker of the competing claims) yielding expected results (connection of the components of the construct). As this is a very common linker, an artisan in this field would attempt this modification with a reasonable expectation of success.
Finally, it would be obvious to add the acetophenone hydrazone of Leamon et al, to allow for cleavage in an acidic environment. Alternatively, this is a substitution of the cleavable linker of Gayraud et al for the cleavable linker of Leamon et al, yielding expected results of an acid labile linker. As Leamon et al shows that targeting a drug can improve it’s toxicity profile, an artisan in this field would attempt this substitution with a reasonable expectation of success.
Conclusion
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658
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