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 with traverse of Group I, claims 1-12, 14, and 15 in the reply filed on 2/5/2026 is acknowledged. The traversal is on the ground(s) that CN103044521 A, cited in the Restriction Requirement, does not include [(CH2)pO]q- as recited in claim 1. This is found persuasive and the restriction requirement is hereby withdrawn.
Claim Status
Claims 1-12, 14-17, and 19-20 are pending under examination. Claims 1, 4, 15, 16, 19, and 20 are currently amended. Claims 15, 16, 19, and 20 are objected to for improper multiple dependency and not further examined on the merits, see below under Claim Objections.
Priority
The instant application is the 371 national stage entry of PCT/CN21/77056, filed 2/20/2021, which claims priority to CN202010106067.9, filed 2/20/2020. The priority date of 2/20/2020 is acknowledged although it is noted that no translation has been made of record.
Drawings
The drawings are objected to because 1) Figures 3 and 7, it is unclear what the units are of the Y-axis and it is difficult to determine which line corresponds to which compound in the key as everything is in grayscale; 2) Figures 4, 10, and 11 are lacking scale bars; 3) Figures 8 and 9, each of the X-axis labels is slightly shifted to the left relative to its corresponding bar; and 4) Figure 12, it is unclear what each of the individual lines represents (different mice?). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Figure 1 should be designated by a legend such as --Prior Art-- because only that which is old is illustrated. See MPEP § 608.02(g). Corrected drawings in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. The replacement sheet(s) should be labeled “Replacement Sheet” in the page header (as per 37 CFR 1.84(c)) so as not to obstruct any portion of the drawing figures. If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
1. Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825 because it does not contain a "Sequence Listing" as a separate part of the disclosure or a CRF of the “Sequence Listing.”.
Required response - Applicant must provide:
A "Sequence Listing" part of the disclosure; together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(a)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.821(a)(4); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(a)(3).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
If the "Sequence Listing" part of the disclosure is submitted according to item 1) c) or d) above, applicant must also provide:
A CRF in accordance with 37 CFR 1.821(e)(1) or 1.821(e)(2) as required by 1.825(a)(5); and
A statement according to item 2) a) or b) above.
2. Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
3. Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
4. Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
The compound EMC-AANL-DOX has four specifically defined and enumerated amino acids (“AANL”) and appears throughout the specification and drawings. The inclusion of this peptide requires the above, 1-4.
Specification
The use of the term Tween (Pg 31-32), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 2, 5, 6, 9, and 11 are objected to because of the following informalities:Claim 2 recites “among them” in reference to a maleimide group (emphasis added).
Claims 5, 6, 9 both recite multiple compounds without commas separating each one.
Claim 11 recites compounds a and b, but part of compound b is cut off by the label for compound a, shown here:
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Appropriate correction is required.
Claims 15, 16, 19, and 20 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot depend from any other multiple dependent claim. See MPEP § 608.01(n). Accordingly, the claims have not been further treated on the merits.
Claim Interpretation
Claim 5 recites MI, S1, S2, S3, C, and A are all connected to each other through various connections. Because claim 5 ultimately depends from claim 1, which recites that S1 and S3 can be absent, the claim has been interpreted as the connections of MI-S2, S2-C, and C-A.
Claim 17 recites a method of applying the compound of any one of claims 1-10, wherein the application results in an outcome that occurs as a result of the structure of the compound. Consequently, the claim is being interpreted based upon the structural features of the compound, namely, a compound as recited in any one of claims 1-10; therefore, any application of said compound reads on claim 17.
Claim Rejections - 35 USC § 112
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 1-11, 14, and 17 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 claim 1, the phrase "such as" in line 11 renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Additionally, claim 1 recites that A is the auxiliary linker. There is no definition for this term in the instant specification, and it is unclear what, structurally, an auxiliary linker is. Therefore, the claim is indefinite. For purposes of examination, and auxiliary linker is being interpreted as any additional moiety that may or may not be conjugated to another moiety.
Additionally, claim 1 recites that S2 is selected from PEG linkers with variables p and q, wherein p is an integer of 1-4, preferably 2, and q is an integer of 1-15, preferably 2-6. Claim 1 also recites that S3 is selected from polar amino acids, preferably Glu and Asp. The scope of this claim is indefinite because it is unclear whether p and q of S2 can be any of 1-4 or 1-15 or is limited to 2 or 2-6, respectively. Likewise, regarding S3, it is unclear whether S2 is open to any polar amino acid or limited to only Glu and Asp. For purposes of examination, the claim is being interpreted as p and q are both open to their broadest ranges of 1-4 and 1-15, respectively, and S3 is any polar amino acid.
By virtue of their dependency on claim 1, claims 2-10, 12-14, and 17 are also hereby rejected for this same reasoning.
Further, claims 4, 8, 10, and 11 recite similar “preferably” and/or “more preferably” limitations. For each of these claims, the scope of the claim is being interpreted as the broader scope recited before preferably:
For claim 4, R4 is selected from Glu, Asp, Gly, Ala, Val, Leu, Ile, Met, Phe, Trp, Ser, Thr, Cys, Tyr, Asn, Gln, Lys , Arg and His and is attached in any way; and p and q are as recited in claim 1;
For claim 8, X3 is L or D Asn and X1X2X3 is selected from any combination of L and D amino acids as set forth in lines 1-2;
For claim 10, C is any proteolytic enzyme cleavable amino acid linker tripeptide; and
For claim 11, A and D are linked as described in any of claims 1-10.
Claim 3 recites that is S is attached to C through a group selected from four compounds, wherein each compound has two wavy lines to represent their connection points. The scope of this claim is indefinite as it is unclear which part of each compound is connected to S and C as not all of the compounds are symmetrical. For instance, using the first compound as an example, is S attached to the left side of the molecule and C to the right side or vice versa? For purposes of examination, the claim is being interpreted as S and C can be on either the left or the right side of each of the compounds depicted. Claims 5 and 11 recite similar limitations and are also rejected for this same reasoning. Additionally, claim 14, which depends on claim 11, also hereby rejected for this same reasoning. For each of these claims, the scope of the claim is being interpreted as the relative orientation of the linking compound can have any of two of the adjacent components on either side.
Claim 7 recites the limitation “a group that expresses asparagine endopeptidase cleavage in the tumor microenvironment”. Such a group is not defined in the instant specification and it is unclear what is included in said group and what the structural features of it are. Thus, the claim is indefinite. For purposes of examination, the claim is being interpreted as an amino acid sequence that is recognized and cleaved by a proteolytic enzyme.
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.
Claims 2 and 5 are 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.
Claim 2 recites that MI is a maleimide group with the structure depicted. This does not further limit claim 1, from which claim 2 depends, as claim 1 also recites that MI is a maleimide group.
Claim 5 recites that MI, S1, S2, S3, C, and A are connected to each other through different linking groups. None of these groups are recited in the MI-S-C-A structure of claim 1, from which claim 5 depends. Thus, claim 5 is broader than base claim 1.
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) 1-4, 6-9, 11-12, 14, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Cazzamalli et al. (In Vivo Antitumor Activity of a Novel Acetazolamide-Cryptophycin Conjugate for the Treatment of Renal Cell Carcinomas. ACS Omega. 2018 Nov 30;3(11):14726-14731.) in view of Liu et al. (US 9982011 B2, published 5/29/2018).
Cazzamalli teaches small-molecule drug conjugates (SMDCs) are useful alternatives to antibody-drug conjugates in that their small size facilitates rapid and uniform diffusion into tissues, they have lower cost-of-goods, lack of immunogenicity, amenability to chemical synthesis, and easier analytical characterization (Pg 14726, left column, second paragraph).
Cazzamalli teaches the following SMCD:
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wherein AAZ+ is a delivery vehicle for tumor targeting, ValCit is a cleavable dipeptide with para-aminobenzyl self-immolative part, and cryptophycin-55 glycinate is the anticancer drug (Pg 14726, right column, first paragraph – Pg 14727, right column, “Results and Discussion,” first paragraph). The ValCit-PAB linker is attached to AAZ+ via a triethylene glycol spacer containing a maleimide moiety designed to increase the solubility of the conjugate and facilitate the conjugation to the acetazolamide moiety (Pg 14727, “2. Results and Discussion,” first paragraph – Pg 14728, left column, first paragraph).
Cazzamalli does not teach that the AAZ+-VitCit-Cry55Gly compound, as shown above, has a maleimide group.
Liu teaches conjugates of doxorubicin derivatives for targeted activation by legumain (Abstract). Liu teaches that doxorubicin and epirubicin are commercially available anti-tumor drugs with broad anti-tumor spectrum that can have serious side effects (Col. 1, lines 34-48). To reduce toxicity, efforts have been made to enhance the biological specificity and selectivity of anti-tumor drugs. The targets for the disclosed doxorubicin derivatives are cathepsin and legumain, which are proteolytic enzymes highly expressed in tumors but lowly in normal tissues. The doxorubicin derivatives disclosed target the tumor microenvironment and are activated as specific substrates of legumain, which effectively hydrolyzes and activates the compound only in this local area, thereby releasing its cytotoxicity (Col. 5, lines 12-48). The compound taught by Liu is
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, where R3 is Leu or not present, R4 is Ala or Thr; R5 is Ala, Thr, or Asn; and R6 is a functional group that improves the half-life of drug metabolism, such as
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(Abstract). Legumain can cleave the peptide fragment by hydrolysis at the position before Asn to release doxorubicin/epirubicin-Asn or doxorubicin/epirubicin (Col. 6, lines 20-24).
In summary, Cazzamalli teaches SMDCs comprising S-C-A-D, as described above. Liu teaches similar SMDCs that are specifically targeted and activated by legumain, which is highly expressed in cancer cells; to improve the half-life of the drug, Liu teaches the addition of a maleimide group, shown above.
Based on these teachings, regarding claims 1 and 2, it would be prima facie obvious to incorporate the maleimide group taught by Liu into the AAZ+-VitCit-Cry55Gly compound taught by Cazzamalli. One skilled in the art would be motivated to do so in order to improve the half-life of the drug. One would have a reasonable expectation of success as Liu teaches that this strategy is an effective approach for similar drug-conjugates with cleavable peptide linkers.
Regarding claims 3 and 4, as shown above, Cazzamalli teaches the following:
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. This meets the limitations of claim 3, wherein the attachment is through the carbonyl group, and claim 4, wherein R1 is absent, p is 2, q is 4, R2 is C2 alkylene, R3 is -C(O)R4-, and R4 is absent.
Regarding claim 6, Cazzamalli and Liu teach MI-S corresponding to the following
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, wherein MI-S is directly conjugated to an amino acid.
Regarding claims 7 and 8, Liu teaches that C, shown above, can consist of the tripeptide AAN (Abstract).
Regarding claim 9, as shown above, Cazzamalli teaches A is PABC-OH conjugated via a carbonyl group to the drug cryptophycin-55 glycinate:
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.
Regarding claim 11, as stated above, Liu teaches doxorubicin as the drug attached to the conjugate and A and D are attached via
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.
Regarding claim 12, Cazzamalli and Liu teach the instant compound
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(instant Pg 14, 4th compound down from top).
Regarding claim 14, Liu teaches that the addition of serum albumin to the R6 group
described above further increases the solubility of the compound (Col. 7, line 12-15).
Regarding claim 17, Liu teaches application of the disclosed compounds in the preparation of anti-tumor drugs (Abstract).
Claim(s) 1-9, 11-12, 14, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Cazzamalli et al. (In Vivo Antitumor Activity of a Novel Acetazolamide-Cryptophycin Conjugate for the Treatment of Renal Cell Carcinomas. ACS Omega. 2018 Nov 30;3(11):14726-14731.) and Liu et al. (US 9982011 B2, published 5/29/2018). as applied to claims 1-4, 6-9, 11-12, 14, and 17 above, and further in view of Cortez et al. (WO2018198091A1, published 11/1/2018; partial document attached due to size).
The teachings of Cazzmalli and Liu have been set forth above. Cazzamalli further teaches that S2-C and C-A are connected via carbonyl groups, as shown above. Cazzamalli and Liu do not teach that MI-S2 are connected to each other through any of the groups listed in claim 5.
Cortez teaches antibody conjugates and their uses in the treatment of cancer (Abstract). Cortez teaches the following compound:
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(Pg 28), in which the maleimide group is attached to PEG via
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, which is the first connection group recited in claim 5.
In summary, Cazzamalli and Liu teach drug-conjugates comprising the formula MI-S-C-D, in which S2-C and C-D are connected to each other via carbonyl groups. Cortez teaches similar drug-conjugates wherein the maleimide group is connected to the PEG linker via
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. Therefore, regarding claim 5, it would be prima facie obvious to connect the maleimide group of MI to S2 via the group taught by Cortez. One skilled in the art would be motivated to do so and have a reasonable expectation of success as Cortez teaches this connection can be used to generate similar types of drug-conjugates designed to treat cancer.
Claim(s) 1-4, 6-12, 14, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Cazzamalli et al. (In Vivo Antitumor Activity of a Novel Acetazolamide-Cryptophycin Conjugate for the Treatment of Renal Cell Carcinomas. ACS Omega. 2018 Nov 30;3(11):14726-14731.) and Liu et al. (US 9982011 B2, published 5/29/2018). as applied to claims 1-4, 6-9, 11-12, 14, and 17 above, and further in view of Liu et al. (“Liu2,” CN104262455A, published 8/22/2014; rejection based on English translation attached).
The teachings of Cazzamalli and Liu have been set forth above. Cazzamalli and Liu do not teach the compounds described in the Table of claim 10 but do teach A is PABC-OH, as shown above.
Liu2 teaches tumor microenvironment targeted activation of paclitaxel derivatives with the following structure:
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, where R1 is Ala, Thr, Val, or Ile; R2 is Ala, Thr, Val, or Asn, and n=1-300 (Abstract; see original document first page for structure). Liu2 teaches that paclitaxel is a widely used cancer drug with serious side effects ([0002]). To improve the side effects and limit its toxicity, paclitaxel is combined with an appropriate compound that can aggregate at tumors and release paclitaxel ([0003]). Liu2 teaches that the short peptides contained in the conjugate act as a linker that are cleaved by enzymes in the tissue tumor, leading to highly efficient release and activation of paclitaxel ([0022]). Liu2 teaches that n is preferably 1-150 ([0024]).
In summary, Cazzamalli and Liu teach drug conjugates with the formula MI-S-C-A-D, wherein S comprises tetraPEG. Liu2 teaches similar anticancer drug conjugates comprising PEG, a peptide cleavable linker may of similar amino acid sequences, PABC-OH, and paclitaxel.
Based on these teachings, compounds QHL-005 through 008 of the instant claim 10 are rendered obvious. One skilled in the art would be motivated to generate said compounds by replacing the [(CH2)pO]q-CH2CH2CO linker with PEG. One would have been motivated to do so and had a reasonable expectation of success as Liu2 demonstrated that similar compounds could incorporate PEG at the same relative position to release and activate paclitaxel in the treatment of cancer.
Regarding claim 11, as stated above, Liu2 teaches paclitaxel.
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.
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Claims 1, 2, 7, 8, 11, 15 and 17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4-7, and 9-14 of U.S. Patent No. 9,982,011 B2 (US ‘011) in view of Cazzamalli et al. (In Vivo Antitumor Activity of a Novel Acetazolamide-Cryptophycin Conjugate for the Treatment of Renal Cell Carcinomas. ACS Omega. 2018 Nov 30;3(11):14726-14731.).
Claim 1 of US ‘011 recites a doxorubicin derivative for targeted activation by Legumain, having the following structural formula:
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, wherein the doxorubicin derivative is prepared by condensation between the amino group of compound A and the carboxyl group of compound B, and compounds A and B have the following structures, respectively:
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, wherein R3 in compound B is Leu or absent; if R3 is absent then compound B is a tripeptide, that is, the carboxyl of Asn covalently condensates with the amino of compound A directly to produce a polypeptide doxorubicin; if R3 is Leu then compound B is a tetrapeptide, that is Leu-Asn-R4-R5-; R4 is any one amino acid selected from the group consisting of Ala and Thr; R6 is
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, wherein n = 1-20; or
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, wherein R7 is substituted or unsubstituted, linear or branched, saturated or unsaturated C1-C20 fatty hydrocarbon, or substituted or unsubstituted C6-20 aromatic hydrocarbon.
Dependent claims further include additional doxorubicin derivative drugs (claims 2, 4, 5), the preparation of anti-tumor drugs and/or a medicament (claims 9 and 12), the sequence of the cleavable linker (claims 10 and 11), methods of preparation thereof (claims 6 and 7), and methods of treating cancer (claims 13 and 14). The instant specification teaches that the compounds can be used to treat the species of cancer recited in claim 14 of US ‘011 (see instant Pg 34, lines 11-25).
US ‘011 does not teach a PEG linker as part of MI-S, shown above.
Cazzamalli teaches similar anticancer drug conjugates comprising a PEG linker, a peptide cleavable linker, PABC-OH, and a drug.
Therefore, it would be prima facie obvious to one of ordinary skill in the art to incorporate the teachings of Cazzamalli into US ‘011, thereby arriving at the instant invention. One skilled in the art would have a reasonable expectation of success as Cazzamali demonstrates that PEG can be incorporated into similar compounds to release and activate drugs to treat cancer. Thus, the claims are obvious in view of US ‘011.
Claims 1-12, 14 and 17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 11,319,341 B2 (US ‘341) in view of Cazzamalli et al. (In Vivo Antitumor Activity of a Novel Acetazolamide-Cryptophycin Conjugate for the Treatment of Renal Cell Carcinomas. ACS Omega. 2018 Nov 30;3(11):14726-14731.).
Claim 1 of US ‘341 recites a compound represented by the following formula I or a pharmaceutically acceptable salt thereof: MI-S-C-A-D, wherein MI represents a maleimide group covalently group covalently coupled to plasma albumin; S represents a selective group wherein the selective group improves the efficiency of enzyme digestion or selectivity; C represents a cleaving group wherein the cleaving group is an amino acid linker that a proteolytic enzyme can break and wherein C is selected from the following group consisting of: Ala-Ala-Thr, Thr-Ala-Asn, Val-Ala-Asn, Asn-Ala-Asn, Thr-Thr-Asn, Val-Thr-Asn, Asn-Thr-Asn, Ala-Val-Asn, Thr-Val-Asn, Val-Val-Asn, Asn-Val-Asn, Ala-Ile-Asn, Thr-Ile-Asn, Val-Ile-Asn, Asn-Ile-Asn, Ala-Thr-Asn, D-Thr-L-Val-L-Asn, D-Thr-L-Ala-L-Asn, D-Ala-L-Val-L-Asn, L-Thr-D-Val-L-Asn, L-Thr-D-Ala-L-Asn, L-Ala-D-Val-L-Asn, D-Thr-D-Val-L-Asn, D-Thr-D-Ala-L-Asn, and D-Ala-D-Val-L-Asn; A represents an auxiliary connecting arm; and D is a doxorubicin or epirubicin.
Dependent claims include species of the maleimide group (claim 2), species of MI-S (claims 3-4), species of A (claim 5), and species of the compound as a whole (claims 6-7). The specification of US ‘341 teaches application of the disclosed compounds (see Col. 2, lines 20-26).
US ‘341 does not teach a PEG linker as part of MI-S, shown above.
Cazzamalli teaches similar anticancer drug conjugates comprising a PEG linker, a peptide cleavable linker, PABC-OH, and a drug.
Therefore, it would be prima facie obvious to one of ordinary skill in the art to incorporate the teachings of Cazzamalli into US ‘341, thereby arriving at the instant invention. One skilled in the art would have a reasonable expectation of success as Cazzamali demonstrates that PEG can be incorporated into similar compounds to release and activate drugs to treat cancer. Thus, the claims are obvious in view of US ‘341.
Conclusion
No claim is allowed.
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/SARA E KONOPELSKI SNAVELY/Examiner, Art Unit 1658
/FRED H REYNOLDS/Primary Examiner, Art Unit 1658
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