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 .
Status of the Application
The claims of 22 October 2024 are entered.
Claims 1-7, 16-26, and 35-38 have been canceled. Claims 8-15, 27-34, 39, and 40 are pending.
Claim Rejections - 35 USC § 112
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 8-15, 27-32, 34, and 39-40 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of selectively inhibiting human immunoproteasome 20S β5i active site over human constitutive proteasome β5c active site with specific compounds of formula (I) (compounds 1-12, 17, 30, 31, 36, 37, 40, and 43 as in claim 14 or the compounds as in claim 33) does not reasonably provide enablement for a method of selectively inhibiting human immunoproteasome 20S β5i active site over human constitutive proteasome β5c active site with generic compounds of formula (I), (Ia), (Ib), or (Ic). 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 use the invention commensurate in scope with these claims.
“[T]o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation.’” Genentech Inc. v. Novo Nordisk 108 F.3d 1361, 1365, 42 USPQ2d 1001, 1004 (Fed. Cir. 1997); In re Wright 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); See also Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 1212, 18 USPQ2d 1016, 1026 (Fed. Cir. 1991); In re Fisher 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). Further, in In re Wands 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988) the court stated:
Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman [230 USPQ 546, 547 (BdPatAppInt 1986)]. They 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 unpredict-ability of the art, and (8) the breadth of the claims.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Nature of the Invention
The invention is drawn to a method of inhibiting specific human immunproteasomes, in particular the human immunoproteasome 20S β5i active site over human constitutive proteasome β5c active site with compounds of formula (I). The compounds of formula (I), along with sub-formulas (Ia), (Ib), and (Ic) are all dipeptidomimetics.
Breadth of the Claims
The claims are broad with respect to the claimed compounds of formulas (I), (Ia), (Ib), and (Ic). The most generic constructs provide a dipeptide-like framework but allow for variability along all non-backbone atoms and two backbone positions. The compounds encompass an incalculable number of options given the high variability for the claimed R4, L, Y, M, X, and R1 positions in formula (I). The compounds of formulas (Ia), (Ib), and (Ic) are more restricted but still offer an extremely broad genus given the options for R4, Rx, R3, Y, R2, Ry, X, and R1. As disclosed in claim 14, the breadth of the compounds includes those where protecting groups such as Boc and Bn are still present, as well as TFA salts.
State of the Prior Art
With respect to those compounds encompassing TFA salts, the art recognizes that TFA salts of peptides are generally not useful for biological assays such as determining impact on immunoproteasome activity, since TFA is cytotoxic at nanomolar concentrations (see e.g. https://lifetein.com/blog/should-i-have-tfa-removed-from-my-peptide). The post-filing LifeTein art also indicates that TFA can interfere with enzymatic assays due to the strong acidity of the TFA, again suggesting that a TFA salt would not be useful in methods of inhibiting human immunoproteasome.
Relative Skill of those in the Art
The relative skill of those in the art is high.
Predictability or Unpredictability of the Art
There is a general lack of predictability in the pharmaceutical art. In re Fisher, 427, F. 2d 833, 166, USPQ 18 (CCPA 1970).
The impact of a protecting group on a given dipeptidomimetic is not predictable, i.e. whether compounds such as compounds 13, 14, and others in claim 14 that preserve Boc or Bn protecting groups would exhibit selectivity towards the human immunoproteasome 20S β5i active site over human constitutive proteasome β5c active site. Notably, none of the data on proteasome selectivity as presented in the specification consider a protected form of any of the dipeptidomimetics (see e.g. Example 67).
Amount of Direction or Guidance Given
The specification guides that it is preferable that the compounds be administered as a pharmaceutical composition (see [0064]). Generally this requires removal of protecting groups. Furthermore, the [0064] states that a pharmaceutically acceptable salt be present, and as noted above TFA salts of peptides are not generally considered to be pharmaceutically acceptable.
Presence/Absence of Working Examples
The Examples largely show synthesis of compounds as found in claims 14 and 33. While compounds are produced during the Examples with protecting groups, all examples immediately following demonstrate removal of the protecting groups. Example 67 is the only example that considers activity of the various dipeptidomimetics with respect to proteasome inhibition.
In Example 67, eighteen constructs were tested for their inhibitory activity towards the human i-20s and human c-20s proteasomes. The text describing the results specifically states that “..compounds with substituents at amide side chain of the Asparagine (2nd amino acid from C-terminus) and C-terminal caps allowed the resulting dipeptides to selectively inhibit the human immunoproteasome β5i active site over the human constitutive β5c active site” (see e.g. [0153]). However, the amide substituents as disclosed are a small portion of what is encompassed by formulas (I), (Ia), (Ib), and (Ic). PKS2295 is reported as having a logP of 0.69, but the results also indicate that and IC50 for the c-20S active site was not determined. PKS2292 and PKS3065 are both reported such that the IC50 for both is over 100 µM, indicating weak affinity at best for both immunoproteasomes.
Quantity of Experimentation Necessary
The skilled artisan is presented with very broad compounds as encompassed by formulas (I), (Ia), (Ib), and (Ic). This alone might be merely a matter of routine experimentation, but combined with the need to evaluate the broad genus for activity in view of highly limited examples poses an undue burden on the part of the skilled artisan. As discussed above, the variables within each of the claimed generic formulas is such that one cannot easily ascertain the number of species within each genus. There are at best 18 specific constructs that were prepared and tested, and at least one cannot clearly be viewed as possessing the claimed activity since there was no data on inhibition of one active site of immunoproteasome. Two others indicate very weak inhibition of both human immunoproteasome active sites. Given this data and the limited guidance on the genus, the onus is left largely on the part of the skilled artisan to examine the breadth of the genus for the claimed selectivity for one site over the other. Such an effort is beyond the level of routine experimentation considering the breadth of the claims.
In view of the Wands factors as discussed above, it is the Examiner’s opinion that the claims are not fully enabled and one of skill in the art would have to engage in undue experimentation to practice the invention as claimed herein, without a reasonable assurance of success.
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 14 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. Claim 14 recites a number of dipeptidomimetics as TFA salts. For instance, see the 14th compound. Claim 8 does not recite any salt forms of the claimed dipeptidomimetics within the method of use. Accordingly, recitation of a TFA salt serves to broaden the claim beyond the scope allowed for by claim 8. 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 § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 8-13, 15, 27-30, 34, 39, and 40 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Lin et al. (US 2017/0121366 A1, published 4 May 2017, priority to 10 January 2014, hereafter referred to as ‘366).
The ‘366 application claims a compound of formula (I) that is a subgenus of the instantly claimed formula (I) (see e.g. claim 1). The ‘366 art does not explicitly claim formula (I) as being selective for the human immunoproteasome 20S β5i active site over the human constitutive proteasome β5c active site. However, when discussing formula (I) and the compounds encompassed therein, the ‘366 application states that they are the “…first inhibitors that act both with high selectivity and full reversibility on hu i-20S β5i over hu c-20S” (see e.g. [0040]). Therefore, since ‘366 discloses a subgenus within formula (I) and an overlapping use, it anticipates claim 8.
With respect to claim 9, the ‘366 compound is again a sub-genus of the claimed formula.
With respect to claim 10, the ‘366 application claims aromatic groups at R1 encompassing the options as claimed such as a monocyclic or bicyclic aryl.
With respect to claim 11, the ‘366 application claims overlapping options for R2.
With respect to claim 12, again the ‘366 application claims a subgenus overlapping with R3.
With respect to claim 13, ‘366 claims overlapping R4 within its subgenus.
With respect to claim 15, the ‘366 application also claims that the subject can have cancer, immunological disorders, inflammatory disorders, or requires immunosuppression to prevent transplant rejection (see e.g. claim 8).
With respect to claims 27 and 28, again as set forth above the ‘366 application claims a subgenus covering formula (I), including (Ia) through (Ic).
With respect to claims 29-32, as set forth above the ‘366 application formula overlaps with R1, R2, R3, and R4.
With respect to claim 34, as set forth above the ‘366 application claims treatment of overlapping subjects.
With respect to claims 39 and 40, the ‘366 application also discloses treatment of overlapping conditions (see e.g. claims 15-22).
Allowable Subject Matter
Claim 33 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter: the compounds as found in claim 33 are free of the prior art. The above cited Lin et al. US 2017/0121366 A1 art discloses a subgenus encompassing the generically claimed compounds, but offers no particular motivation to prepare any of the compounds as found in claim 33. No other prior art discloses dipeptidomimetics as claimed that selectively inhibit the human immunoproteasome 20S β5i active site over the human constitutive proteasome β5c active site. The claimed method is novel and unobvious pending consideration of any amendment Applicants may make in response to this action.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY J MIKNIS whose telephone number is (571)272-7008. The examiner can normally be reached M-F 9-5.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melissa Fisher can be reached at (571) 270-7430. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ZACHARY J MIKNIS/Patent Examiner, Art Unit 1658