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 .
DETAILED ACTION
Response to Election/Restriction filed on April 23, 2026 is acknowledged. Claims 1-18, 20-22 are pending in the instant application.
Election/Restrictions
Applicant elected without traverse Formula Ia, G2B-001 (claim 13); L is linker A; SEQ ID NO:8 is P; S is 0; W is absent and Y is NH2,
The restriction is deemed proper and is made FINAL in this office action. Claims 3, 11-12, 14-17 are withdrawn from consideration as being drawn to a non-elected species.
Claims 1-2, 4-10, 13, 18 and 20-22 are examined on the merits of this office action.
Claim Objection
Claim 1 is objected to for the following informality: in sections “(b)”, “(c)” and “(d)”, it is suggested that “are equal” be replaced with -are the same-. Furthermore, in sections “(b)”, “(c)” and “(d)”, “cysteines”, “selenocysteines” and “penicillamines” should all be in the singular. Furthermore, in section (d), it is clear based on the specification and sequence listing that “and X8-X10” should be X8 and X10 are equal.
Claim 2 is objected to for the following informality: the limitation of “attached to a linker L” should be replaced with -attached to the linker L- given claim 1 already recites a linker L and there is only one L in the formula.
Claim 4 is objected to for the following informality: in section (b) the disulfide bond is misaligned and should be between the cysteine residues. Correction is required. Furthermore, please insert an “and” at the end of (d) prior to (e) to recited proper Markush claiming.
Claim 5 is objected to for the following informality: the end if the parenthesis is missing after SEQ ID NO:10. Correction is required.
Claim 20 is objected to for the following informality: Claim 20 should be amended as follows : A method of treatment of a mammal suffering from cancer, said method comprisingadministering to said mammal
Claim 22 is objected to for the following informality: acronyms should be spelled out in their first instance. For example, Diffuse intrinsic pontine glioma (DIPG). Correction is required.
Claim 1 claims “chemically feasible bond” in multiple instances. The term "chemically feasible" is an unnecessary term and may introduce ambiguity. In the instant case, the bond is defined but it is suggested that the term be removed to improve claim clarity.
Claim Rejections - 35 USC § 112, First Paragraph
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2, 4-10, 13, 18 and 20-22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
Scope of the claims
The claims define a pharmaceutical conjugate comprising an SN-38 payload Z, a linker L, and a targeting peptide (P). The claimed linker L is defined as a modular biradical composed of two to eight linker fragments according to L=La’-(Lb’)n-Lc’ wherein La’, Lb’, and Lc’ are independently selected from extensive Markush groups comprising numerous chemical functionalities, including amides, esters, carbamates, ethers, thioethers, sulfones, phosphates, silanes, triazoles, maleimides, peptide containing linkers, aromatic spacers and related structures. The specification further depicts at least 15 expressly illustrated as linkers L1-L15. The resulting claim scope encompasses a very large genus of potential linkers through independent selection of linker fragments and optional repetition of intermediate linker units. The claims therefore extend beyond the examples shown in the specification. The desired function is therapeutic use as a pharmaceutical composition capable of delivering SN-38 to target cells through peptide mediated targeting and treating cancer,
Therefore, to meet the written description requirement of 35 U.S.C. § 112, first paragraph, the specification must disclose a representative number of species that meet both the structural and functional limitations of the genus or the specification and/or the prior art must identify the structural elements that correlate to the claimed function in a manner that demonstrates to one of ordinary skill in the art that Applicant was in possession of the claimed genus at the time the application was filed.
Actual Reduction to Practice
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The specification demonstrates actual synthesis and testing of several linker classes including triazole click linker (Linker A); Linker B; Linker TTDS; diglycolic linker; glycine carbamate linker; Val-Cit-PAB linker. Thus, several linker types were reduced to practice, however, the number of experimentally demonstrated linker chemotypes remains relatively small compared with the linkers encompassed by claim 1. Furthermore, the specification discloses several linkers, including linkers A and N, and demonstrates that linker structure affects biological activity. However, these few disclosed linkers represent only a small subset of the broad linker genus encompassed by the claims, providing limited evidence of possession of the full claimed scope.
Sufficient relevant identifying characteristic
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination thereof.
The specification provides structural information regarding specific compounds. The specification identifies numerous linker structures (L1-L15). Although the specification supplies structural identifying characteristics for specific members, this is not sufficient for the claimed genus.
Physical/Chemical Properties
For the synthesized compounds, the specification shows many physical and chemical properties. In particular, G2B-001 was stable in human serum for at least 24 hours; plasma recovery after 24 hours exceeded approximately 60-70% depending on species; linear G2B-0001 showed greater than 24 hour stability. These data established that that the disclosed linkers can be used to produce stable conjugates. However, comparable physical and chemical property data are not provided for most of the potential linker combinations encompassed by the claims.
Functional characteristics when coupled with a known or disclosed correlation between function and structure:
The desired function of the claimed compound and linker is to produce therapeutically useful pharmaceutical conjugates capable of delivering SN-38 while maintaining stability, having anti-cancer activity, peptide targeting and use in a pharmaceutical setting. The examples reduced to practice in the specification establish a correlation between specific linkers and therapeutic function. However, the specification also demonstrates variability among linkers as well. Example 12 directly compares Linker A and Linker B and concludes that linker identity affects biological function. This shows that not all linkers falling within the broad genus have equivalent or desired functional activities.
Method of Making
The specification does not provide synthetic examples for most of the potential linker combinations encompassed by the claims. Instead, the specification relies upon generalized synthetic methods and the ordinary skill of medicinal chemists to extend the chemistry beyond the exemplified embodiments.
Conclusion
While the specification provides structural descriptions and enabling synthetic methods, the experimental evidence establishes therapeutic function for only a relatively small subset of the claimed linker genus (and variability thereof). Accordingly, the written description supports specific linker classes but not for the entire breadth of the claimed genus.
Claims 20-22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), paragraph, because the specification, while being enabling for treatment of specific cancer types with specific conjugates does not reasonably provide enablement for treatment or prevention against any cancer type. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims. The treatment of cancer generally cannot possibly be considered enabled for the many reasons stated below.
To comply with the enablement requirements of 35 U.S.C. §112, first paragraph, a specification must adequately teach how to make and how to use a claimed invention throughout its scope, without undue experimentation. Plant Genetic Systems N.V. v. DeKalb Genetics Corp., 315 F.3d 1335, 1339, 65 USPQ2d 1452, 1455 (Fed. Cir. 2003). There are a variety of factors which may be considered in determining whether a disclosure would require undue experimentation. These factors include: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The Nature of the Invention/ The breadth of claims
Claim 20 claims “A method of treatment of a mammal suffering from cancer, said method comprising administration to said mammal of a therapeutically effective amount of the pharmaceutical composition as defined in claim 1.” Claim 21 claims “a tumor selected from the group consisting of extracranial solid tumors, eye tumors, and CNS tumors” and ckaun 22 claims “wherein the cancer is selected from the group consisting of adult glioma, pediatric gliomas, retinoblastoma, Ewing sarcoma, DIPG, neuroblastoma, and rhabdomyosarcoma.” The claims encompass treating/preventing any cancer type (claim 20).
The breadth of the claims exacerbates the complex nature of the subject matter to which the present claim is directed. The claims are broad due to the vast number of possible cancers and tumor types encompassed by the claims and given the claim encompasses treatment and prevention. Furthermore, there are numerous subspecies within the species of cancers. For example, cancer is not a single disease, or cluster of closely related disorders.
There are hundreds of cancers, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, something seen especially in, for example, the cancers of the breast, brain and salivary glands. They can occur in pretty much every part of the body. There is not a known one compound that can treat all cancer types given the variability (causes and mechanisms of pathogenesis) in cancer types.
State of the Prior Art
While the state of the art is relatively high with regard to treatment of specific cancer types, the state of the art with regard to using SN38 conjugates to treat/prevent cancers/tumors broadly or lacking. There is no one treatment in the prior art or in the Applicant’s specification that will have anticancer activity against any cancer type or prevent any cancer type.
A review of the relevant art yielded a diverse array of treatment options for those suffering from various forms of cancer. Traditional therapies include chemotherapy, radiotherapy and surgery.
Although SN -38 was known as an anticancer agent (see specification, paragraphs 0017-0022) , the prior art also recognized that therapeutic activity of drug conjugates depends on design including linker, targeting moiety and stability. The prior art did not establish that attaching SN38 to any peptide encompassed by the claims would provide therapeutic efficacy across all claimed cancers.
The Predictability in the art
Cancer therapy is highly unpredictable. The specification itself demonstrates that changes in conjugate structure, including linker architecture, influence biological activity. Furthermore, therapeutic efficacy of targeted drug conjugates is known to vary depending upon target, tumor type and conjugate make up. Accordingly, activity of a limited number of disclosed conjugates cannot not reasonably be extrapolated to treating or preventing any cancer type.
Thus, one cannot reasonably extrapolate to all cancers or to prevention.
The Relative Skill of Those in the Art
Although one of ordinary skill would possess expertise in medicinal chemistry and oncology, such skill would not eliminate the need for substantial testing to determine whether each claimed conjugate effectively treats and prevents cancer.
A skilled artisan in oncology drug development would require pharmacokinetics, toxicology, maximum tolerated dose, in vivo efficacy, tumor penetration etc… none of which are provided.
Amount of Guidance/The Presence or Absence of Working Examples
The specification contains working examples demonstrating activity for a limited number of SN-38 conjugates in selected in vitro pediatric glioma cells and limited in vivo tumor models (HSJD-DIPG-007, HSJD-GBM-001 and a neuroblastoma xenograft model). However, these examples represent only a small subset of the claimed conjugates and cancer indications. The specification does not provide working examples demonstrating therapeutic efficacy across the broad range of cancers recited or encompassed by the claims. There are no working examples of preventing cancer in a subject.
The quantity of experimentation needed
Given the fact that, historically, the development of new cancers drugs has been difficult and time consuming, and especially in view of the factors stated above, the quantity of experimentation needed is expected to be great.
Substantial experimentation would be required to identify which of the numerous claimed SN38 conjugates are therapeutically effective for treating or preventing the broad range of cancers encompassed by the claims. A skilled artisan would need to prepare and evaluate numerous linker, peptide, and conjugate variants across multiple cancer types to determine whether each possess the claimed therapeutic efficacy.
Because the specification does not enable the full scope of treating or preventing cancer across all cancer types and subjects without undue experimentation, claims 20-22 are rejected under 35 U.S.C. 112(a) for lack of enablement.
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 1-2, 4-10, 13, 18 and 20-22 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 claims that “Z” is a radical of the pharmaceutical active ingredient SN38, but does not clearly define the structure of the recited radical. Although the claim further states that Z is attached to linker L by one of the two hydroxyl groups of SN38, it is unclear what structural modification of the SN38 molecule constitutes the recited “radical”. Accordingly, the metes and bounds of Z cannot be determined with reasonable certainty. Dependent claims 2, 4-10, 13, 18, 20-22 are also rejected due to their dependence on claim 1 and not clarifying this point of confusion. Claim 1 additionally states in multiple instances “on the right side of the draw Lb’” and one the “left side of the draw Lc’ formulas”. The Phrase “draw Lb’ formulas and drawn Lc’ formulas is unclear and has no recognized meaning in the art, the claim or specification. Further, it is unclear which specific functional groups constitute the recited “left side” and “right side” of the formulas, such that the metes and bounds of the claimed linker cannot be determined.
Claim 5(a) recites “ the peptide having the amino acid sequence DapKAPETALD with an intrapeptide amide bond between Dap and D and identifies the peptide as SEQ ID NO:7. However, SEQ IDNO:7 defines variable residues Xaa at positions 1 and 9, permitting multiple amino acids at those positions, whereas the claim recites specific amino acid at those positions. Accordingly, it is unclear whether claim 5(a) is limited to the specifically recited peptide sequence or encompasses a more broad sequence represented by SEQ ID NO:7. The scope of the claim cannot be reasonably ascertained. A suggested amendment would could be “the peptide comprising SEQ ID NO:7 wherein Xaa at position 1 is Dap and Xaa at position 9 is Asp or claim SEQ ID NO:8. Claim 6 presents the same issue and thus, is also rejected.
Claim 20 recites the limitation "the pharmaceutical formulation” in line 3. There is insufficient antecedent basis for this limitation in the claim. It is suggested that claim 20 be amended to be dependent on claim 18. Claims 21-22 are also rejected due to their dependence on claim 20 and not further clarifying this issue.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 4-10, 13, 18, 20-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-12, 14-20 of copending Application No. 19/100281 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims SN38 conjugates, conjugated to peptide structures via linkers (see claims 1, 20-22, formula I and Formula II (the SN38) and methods of treating cancer (Claims 20-22). Here is an exemplified conjugate of the claims, an in particular, claim 13.
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The copending application claims substantially the same conjugate platform comprising the same linker and BBB shuttle peptides (see claims 1-8). The copending application further claims the therapeutic payload may be an anticancer pharmaceutical agent (see claim 9) including amptothecines and specifically claims SN38 as the payload (see claim 10) and cancer (claim 15). It would have been obvious before the effective filing date of the claimed invention to employ SN-38 in the conjugates of the instant application because the co-pending application expressly teaches SN-38 as a suitable anticancer payload for substantially the same BBB shittle peptide and linker platform. Although the copending claims require an antibody, they employ the same BBB shittle peptide, linker platform and identify SN-38 as payload. Accordingly, omitting the antibody while retaining the peptide/linker/SN-38 platform would have been an obvious variation that does not render the instant claims patentably distinct. The compound of claim 13 would have been an obvious variation of the conjugates claimed in the copending application (without the antibody) and therefore is not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-2, 4-10, 13, 18, 20-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-20 of copending Application No. 18/852424(reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims SN38 conjugates, conjugated to peptide structures via linkers (see claims 1, 20-22, formula I and Formula II (the SN38) and methods of treating cancer (Claims 20-22). Here is an exemplified conjugate of the claims, an in particular, claim 13.
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The copending application claims substantially the same conjugate platform comprising the same linker and BBB shuttle peptides (see claim 1). The copending application further claims formula Ia (claim 8), which is identical to instant claim 13 and falls within the scope of claim 1; pharmaceutical formulations thereof for treatment of cancer (see clams 14, 16).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Closest Prior Art Made of Record
The closest prior art made of record includes Nonaka (cited in Applicant’s IDS) and LLEDO (WO2015001015A1, cited in Applicant’s IDS). Nonaka teaches SN38 conjugated to Annexin A1 BBB shuttle peptide for treatment of glioma, demonstrating delivery of SN38 across the BBB and antitumor activity. Lledo teaches BBB shuttle peptide constructs for delivery of therapeutic agents across the BBB, including anticancer agents, using specific peptide sequences and linkers. However, Lledo does not specifically disclose SN38 conjugates or the specific linker conjugates of the instant claims. There is not teaching, suggestion or motivation to use the specific linker constructs of the instant case in combination with SN38 with a reasonable expectation of success.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERINNE R DABKOWSKI whose telephone number is (571)272-1829. The examiner can normally be reached Monday-Friday 7:30-5:30 Est.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko Garyu can be reached at 571-270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ERINNE R DABKOWSKI/Primary Examiner, Art Unit 1654
Prosecution Insights