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 .
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. PCT/GB2021/053332, filed on 12/16/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 07Sep2023 and 03Sep2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Status of the Claims
Claims 1,3-4, 7 and 9-23 are pending in the instant application and subject to examination herein.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3-4, 7, and 9-23 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 is directed to a genus of bifunctional molecules, designated as formula (IIab), conforming to a general structure of “TBL-L-Z”, wherein one terminus of the molecule “Z” is a heterobicyclic ring system bearing a 3-substituted-2-cyanopropenoyl group, as shown below:
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Claim 1 defines “TBL” as a “target protein binding ligand”; however, claim 1 does not provide any structure for the “TBL” moiety. The instant Specification defines the “Target Protein Binding Ligand (TBL)” by its function without providing any structure: “binds to the target protein with sufficient binding affinity such that the target protein is more susceptible to degradation or proteolysis than if unbound by the bifunction molecule” (page 37, lines 29-35). According to the Specification, the “Target Protein” may be “any polypeptide or protein which has been selected to be targeted for protein degradation and/or increased proteolysis” (page 34, lines 21-24). By this definition, the function of the “TBL” moiety is indefinite because it is not directed to any discrete population of molecules such that a set of known ligands that would bind to the target molecule(s) is/are known. As the structure of the “TBL” is defined by its function, and the function is indefinite, then the “TBL” moiety is indefinite by both structure and function. Furthermore, according to the prior art, any assumption that a person of ordinary skill in the art would readily envisage a binding ligand for any selected target protein is an unreasonable assumption, as evidenced by Bekes (Bekes, et al.; Nature Reviews Drug Discovery, v21, pp181-200; 2022). Bekes provides a review of the first two decades of discovery in proteolysis-targeting chimera (PROTAC) molecules, bifunctional molecules targeting proteins for proteolytic degradation (page 181, Abstract). Bekes teaches that although “proteins of interest” (POIs) “do not need an enzyme active site, they do need a small-molecule binding site that is approachable by an E3 ligase. Using these sites does not require a high-affinity ligand if coupled to the right E3 ligand, but moderate affinity (≥1-500 nM) is typically needed, and access to the POI surface near the binding site by a recruited E3 ligase is essential. Achieving such binding affinities can often be challenging and has promoted research into alternative degraders1. Selection of the ligand-binding site is particularly important in the case of proteins, where the scaffolding POI may only be partially exposed within a given complex. It may be possible to degrade a POI by targeting a neighboring protein within a protein complex (the bystander effect). This approach may prove useful in degrading scaffolding proteins in which the surface of the POI is mostly buried within the complex51 or the POI is a membrane-associated protein” (page 186).
Thus, a person of ordinary skill in the art would not know the metes and bounds of claim 1 as neither the claim nor the Specification nor the prior art provides the structure for the “TBL” moiety directed at “any polypeptide or protein which has been selected”.
Claims 3-4,7, 9-16 and 19-23 depend directly or indirectly from claim 1 and do not resolve the indefiniteness of the “TBL” moiety.
Regarding claims 1, 3-4, 11 and 22, the term “optionally” renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 12 is directed to a bifunctional molecule, as described in claim 10, “for use in medicine”. Claim 13 further limits claim 12 to wherein the “use comprises the treatment and/or prevention of any disease or condition which is associated with and/or is caused by an abnormal level of protein activity”. Claim 14 further limits claim 12 to wherein the bifunctional molecule is “for use in the treatment and/or prevention of cancer”. As written, these claims are unclear as to whether they are intended as an invention of a composition or a method (with steps to perform). If the claims are for a method (“use”) then they are further unclear as the step(s) for the appropriate “use” of the invention is/are not provided.
Claim 17 is directed to the “use of a moiety Z” as defined in any one of formula (IIab) or (IIaa) in a method of targeted protein degradation. This claim is indefinite because it is unclear whether it is a composition (“moiety Z”) or a method (targeted protein degradation). If the claim is for a method (“use”) then it is further unclear as the step(s) for the appropriate “use” of the invention is/are not provided.
Claim 18 is directed to the “use of a moiety Z as defined in any one of formula (IIab) or (IIaa) in the manufacture of a bifunctional molecule suitable for targeted protein degradation”. This claim is indefinite because it is unclear whether it is a composition (“moiety Z”) or a method or a manufacture. If the claim is for a method (“use”) then it is further unclear as the step(s) for the appropriate “use” of the invention is/are not provided.
Claim 19 is directed to a genus of compounds comprising the “Z moiety” as it is defined in claim 1, and includes a “G moiety” that is “configured to enable attachment of the Z moiety to another chemical structure”. The term “another chemical structure” is not further defined in the claim. This claim is indefinite because while the instant Specification does provide some examples of groups that may be used as the “G moiety” (page 25, lines 21-27 and page 26, lines 1-17), the Specification does not provide any concrete definition that limits the metes and bounds of what could comprise the “another chemical structure” of claim 19, nor any complete definition of what group(s) are contained within the metes and bounds of the “G moiety”.
Claim 21 is directed to a method of making a bifunctional molecule as defined in claim 1. This claim is indefinite as no step(s) is/are provided for the method.
Claim 22 is directed to a “method of obtaining bifunctional molecules” according to claim 1. In this method, step “a” includes “providing a bifunctional molecule”, while the following steps b-e include actions that bear no relation to the purpose of “obtaining bifunctional molecules”, including “contacting a cell with a bifunctional molecule”, “detecting degradation of the target protein in the cell”, “detecting degradation of the target protein in the cell in the absence of the bifunctional molecule”, and “comparing” levels of degradation in the cells having and lacking the bifunctional molecule. This claim is indefinite as it is unclear how steps b-c relate to a method of “obtaining bifunctional molecules”, in particular when the bifunctional molecule is already provided in step a.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 22 is rejected under 35 U.S.C. 101 because the claimed invention is not directed to patent eligible subject matter.
The claim recites the limitation of “comparing the level of degradation of the target protein in the cell contacted with the bifunctional molecule to the level of degradation of the target protein in the absence of the bifunctional molecule; wherein an increased level of degradation of the target protein in the cell contacted with the bifunctional molecule indicates that the bifunctional molecule has facilitated and/or promoted the degradation of the target protein.” This step is a judicial exception because it is an abstract idea insofar that it amounts to a mental process. Per MPEP 2106.04(a)(2), III., “The courts consider a mental process (thinking) that "can be performed in the human mind, or by a human using a pen and paper" to be an abstract idea. CyberSource Corp. v. Retail Decisions, Inc., 654 F.3d 1366, 1372, 99 USPQ2d 1690, 1695 (Fed. Cir. 2011). As the Federal Circuit explained, "methods which can be performed mentally, or which are the equivalent of human mental work, are unpatentable abstract ideas the ‘basic tools of scientific and technological work’ that are open to all.’" 654 F.3d at 1371, 99 USPQ2d at 1694 (citing Gottschalk v. Benson, 409 U.S. 63, 175 USPQ 673 (1972)).” This judicial exception is not integrated into a practical application because it amounts to nothing more than interpreting data. The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because no process is positively recited in which any action is to be performed based on the condition by which the level of degradation of the target protein in the cell contacted with the bifunctional molecule is higher than the level of degradation of the target protein in the absence of the bifunctional molecule, nor is it positively recited how the invention is to be used in the case that the level of the degradation of the target protein in the cell contacted with the bifunctional molecule is lower than the level of degradation of the target protein in the absence of the bifunctional molecule, nor is it positively recited how the invention is to be used when the level of degradation of the target protein is equal in the presence and absence of the bifunctional molecule.
Claim 23 is rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim does not fall within at least one of the four categories of patent eligible subject matter because a “compound library comprising a plurality of bifunctional molecules according to claim 1” is not a process, machine, manufacture, or composition of matter.
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 1,3-4,7, 9-15 and 19-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 16-25 and 29-30 of copending Application No. 19/110,659. Although the claims at issue are not identical, they are not patentably distinct from each other, for the following reasons:
Claims 1 and 16-23 of copending Application No. 19/110,659 claim genera of compounds that encompass the genera of compounds claimed in instant claims 1, 3-4, 7, 9-14 and 19-20;
Claim 24 of copending Application No. 19/110,659 claims a set of compounds disclosed in Table 1 of the Specification of 19/110,659, which includes multiple compounds that anticipate the genera of compounds of instant claims 1, 3-4, 7, 9-14 and 19-20, for example compound “A2”2:
Claim Number(s) of Instant Application
Instant Application
Related Application Number 19/110,659
1
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wherein:
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Claim 25 of copending Application No. 19/110,659 claims a pharmaceutical composition of any of the genera of compounds disclosed in preceding claims therein, and thereby anticipates instant claim 11;
Claim 29 of copending Application No. 19/110,659 claims a method of selectively degrading and/or increasing proteolysis of BRD9 (bromodomain protein 9) in a cell, the method comprising contacting and/or treating the cell with a bifunctional molecule as defined by any of the genera disclosed therein, and thereby anticipates instant claim 15;
Claim 30 of copending Application No. 19/110,659 claims a method of making a bifunctional molecule according to any of the genera of compounds disclosed in preceding claims therein, and thereby anticipates instant claim 21;
Claim 31 of copending Application No. 19/110,659 claims a method of screening the bifunctional molecule according to any of the genera of compounds disclosed in preceding claims therein, and thereby anticipates instant claim 22, because although instant claim 22 is directed to a method of “obtaining” bifunctional molecules rather than screening them, the steps of the method of claim 31 of copending Application No. 19/110,659 anticipate the steps of the method of instant claim 22.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to W. JUSTIN YOUNGBLOOD whose telephone number is (703)756-5979. The examiner can normally be reached on Monday-Thursday from 8am to 5pm. The examiner can also be reached on alternate Fridays.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S. Lundgren, can be reached at telephone number (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Examiner interviews are available via a variety of formats. See MPEP § 713.01. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) Form at https://www.uspto.gov/InterviewPractice.
/W.J.Y./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 Italics added by Examiner for emphasis.
2 (2E)-2-[(E)-5-[(4-{[2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)phenyl]methyl}piperazin-1-yl)methyl]-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-3-(1,3-thiazol-2-yl)prop-2-enenitrile