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
Claims 14-20 are pending and under consideration.
It is noted that prior art does not teach the full monoclonal antibody 4C3 which comprise a heavy chain comprising SEQ ID NO: 3 and a light chain comprising SEQ ID NO: 21; and its recombinant form r4C3 which comprise a heavy chain comprising SEQ ID NO: 37 and a light chain comprising SEQ ID NO: 21. However, the specification does not provide written description support the broadly claimed genus, nor enable the claimed method (see 112(a) rejection below).
Priority
It is acknowledged that this application is a 371 of international Appl. No. PCT/EP2020/079208 filed October 16, 2020.
Acknowledgement is made that this application claims priority to foreign applications: FR1911722, filed October 18, 2019. Certified copies of foreign priority applications have been received as required by 37 CFR 1.55.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
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Information Disclosure Statement
The Information Disclosure Statement filed on 11/21/2022 has been considered and entered by examiner.
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 14-20 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a WRITTEN DESCRIPTION rejection.
Claim 14 is drawn a monoclonal antibody directed against neutrophil proteinase 3 represented by the sequence SEQ ID NO: 1, said monoclonal antibody: being specifically directed against a conformational epitope of said neutrophil proteinase 3; and being capable of inhibiting by at least 30% the production of reactive oxygen derivatives by neutrophils, said production of reactive oxygen derivatives being induced by the presence of autoantibodies directed against said neutrophil proteinase 3. Thus, the claim defines the antibody solely by its functional properties, the functions are:
bind to the PR3 protein having the sequence of SEQ ID NO: 1;
be direct against a conformational epitope of said protein;
be capable of inhibiting by at least 30% the production of reactive oxygen derivatives by neutrophils induced by the presence of autoantibodies directed against said PR3.
In addition, given Broadest Reasonable Interpretation (BRI), the monoclonal antibodies can be monoclonal antibodies with different origins; the monoclonal antibodies can bind to different conformational epitope of PR3. The specification teaches only one monoclonal antibody: 4C3 derived from a suffering from granulomatosis with polyangiitis (GPA), which has the claimed functions (see paragraph [0280] and Examples of instant publication US 2023/0203197 A1). The specification does not teach the structure associated with the recited functions. Thus, the specification does not support the broadly claimed genus.
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, reduction to drawings, 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. (See Federal Register, Vol. 66, No. 4, pages 1099-1111, Friday January 5, 2001, especially page 1106 3rd column). 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. MPEP 2163 II.A.3a.ii.
By the time the invention was made, it is well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three "complementarity determining regions" ("CDRs") which provide the majority of the contact residues for the binding of the antibody to its target epitope. Even a single point mutation in HCDR1 region could lead to antibody lose its binding activity (Ni et al., The Protein Journal, 43, pp. 683-696, July 2024, see Abstract). Thus, the specific antibody disclosed by the specification would not tell structure of other antibodies to PR3 or variants of thereof.
In the instant case, the specification teaches only one monoclonal antibody: 4C3 derived from a GPA patient ([0288]) and its recombinant form r4C3 ([0294-0296]). The specification further shows based on in vitro assays: 1) 4C3 and r4C3 have high affinity to PR3 (Table 2 and Table 3); 2) possible conformational epitope recognized by 4C3 (Figs. 4B-4E; and [0299-0302]); 3) 4C3 does not inhibit PR3 enzymatic activity ([0304]); 4) 4C3 leads to an increase in PR3 expression on the surface of neutrophils (Fig. 9 and [0324]); 5) 4C3 was not able to induce Reactive Oxygen Species (ROS) production, thus 4C3 is not an activating antibody (Fig. 10 and [0325]); 6) 4C3 or r4C3 does not induce an increase in CD11b/CD18 surface expression (Fig. 13 and [0326-0328]); 7) 4C3 can inhibit production of ROS induced by ANCA (anti-PR3 auto-antibodies) (Fig. 20 and [0333-0340]). However, antibody 4C3 does not teach the structure of other monoclonal antibodies which bind to the same conformational epitope or different conformational epitope, or other monoclonal antibodies which have same neutralizing activity to ANCA as 4C3.
An article published September 2020 (Granel et al., Frontiers in Immunology, Vol. 11, Article 573040) from the same research teams discloses that 4C3 is the first non-activating anti-PR3 monoclonal antibody (Abstract). Granel teaches that although 4C3 has all the characteristics of a classic PR3-ANCA, 4C3 appears to be non-pathogenic (page 10, col. 2, bottom para.). Granel further teaches that the non-pathogenic characteristic of 4C3 needs further investigation and non-activation of neutrophils by 4C3 can’t be explained by the nature of the mAb (page 12, col. 2, bridging of paras 1-2). The instant specification shows that the antigen binding portion of 4C3 such as F(ab’)2, which would bind the same conformational epitope as 4C3, shows different function in inducing PR3 expression compared with 4C3 (Fig. 15A). Taken together, the specification and prior art have not established the relationship between the claimed functions and the structure of the antibody. Thus, one of ordinary skilled in the art would not be readily visualize/recognize other antibodies encompassed by claim 14, except 4C3 or r4C3, which have the required properties.
Claim 15 recites HCDRs 1-3 and LCDRs 1-3 of antibody 4C3, but allow variations in CDR regions. As set forth above, any change in CDR regions could potentially change the binding property and/or function of an antibody.
Claims 16-17 recited HCDRs 1-3 and LCDRs 1-3 of antibody 4C3, but allow as many as 20 amino acid variations in variable able regions (claim 16), and allow as many as 90 amino acid variations in heavy chain constant region and as many as 40 amino acid variations in light chain constant region (claim 17). However, in view of the difference between 4C3 and F(ab’)2 of 4C3, as shown by the specification, the portion outside of antigen-binding domain is important to the function of 4C3. Except r4C3, the specification does not show any other variant with claimed function. In addition, mutations in the framework regions (non-CDR areas) can alter the structure and dynamics of the antibody, affecting its ability to bind to its target antigen. For example, even single amino acid change in antigen-distal framework position can result in different conformational space and potentially different binding functions, see § Significance on page E486 of Koenig (Koenig et al., PNAS, E486-E495, Publication Date: 01/05/2017).
Claims 18-20 encompass the same genus of antibodies as claim 14.
The ordinary artisan could reasonably conclude based on a survey of the data shown in the instant specification in support of the breadth and scope of the instant claimed monoclonal antibodies that Applicants were not in possession of the broad genus monoclonal antibodies as claimed. Taken together, the instant specification has not provided a sufficient description for the monoclonal antibody encompassed by the claims. Logically, the specification lacks written description support for the method of using the monoclonal antibody.
Claims 19 and 20 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. This is an ENABLEMENT rejection.
The instant claims are drawn to a method for the early treatment and/or prevention of relapse of granulomatosis with polyangiitis comprising the administration of the pharmaceutical composition comprising the monoclonal antibody of claim 14. The specification discloses one PR3-ANCA neutralizing monoclonal antibody 4C3, which is capable of inhibiting by at least 30% the production of reactive oxygen derivatives by neutrophils induced by PR3-ANCA, based on in vitro assay. However, the specification does not disclose early treating and/or preventing of relapse of GPA with any monoclonal antibody encompassed by claim 14, even 4C3.
To be enabling, the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir.,1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547, the court recited eight factors to consider when assessing whether or not a disclosure would require undue experimentation. These factors are:
1) the quantity of experimentation necessary, 2) the amount of direction or guidance provided, 3) the presence or absence of working examples, 4) the nature of the invention 5) the state of the art, 6) the relative skill of those in the art, 7) the predictability of the art and 8) the breadth of the claims.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108,427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
Nature of invention and breadth of the claims:
The instant claims are drawn to a method for the early treatment and/or prevention of relapse of granulomatosis with polyangiitis (GPA) comprising the administration of the pharmaceutical composition comprising the monoclonal antibody of claim 14. Under BRI, the claims thus encompass innumerous monoclonal antibodies targeting different conformational epitope of PR3.
Relative skill in the art:
The relative skill of those in the art is high with an MD or a PhD.
Level of unpredictability in the art and State of the prior art:
The state of the prior art is such that it involves screening both in vitro and in vivo a large number of antibodies to determine which antibody exhibits the desired therapeutic activities for certain condition, because both binding site and binding affinity are critical for the therapeutic activity of an antibody. As suggested by Granel (Granel et al., Frontiers in Immunology, Vol. 11, Article 573040), the non-pathogenic character of 4C3 seems to be related to its epitope targeted on PR3 (the bridging paragraph of cols. 1-2 on page 14). Thus, antibodies binding to different epitopes of PR3 could have different functions/properties compared to 4C3, indicating unpredictability of therapeutic outcomes with claimed anti-PR3 antibodies. Furthermore, despite the central role of PR3-ANCA in GPA physiology, the correlation between PR3-ANCA level and disease activity is inconsistent (page 2, col. 1, para. 3).
As such, the mere generalized description of antibodies by functional definition cannot always suffice to describe adequately antibodies that have an therapeutic effect for early treating or preventing in the absence of in vivo working example, because the skilled artisan could not immediately predict, recognize, or distinguish those antibodies that bind a conformational epitope with desired therapeutic effect from antibodies that bind a conformational epitope but lacking desired therapeutic effect. Thus the prior art teaches the therapeutic effectiveness of an antibody for targeting GPA is not a certainty, and is determined empirically.
Direction or guidance and working examples:
MPEP § 608.01 (p) provided that within the specification, "at least one specific operative embodiments or examples of the invention must be set forth. Examples and description should be of sufficient scope as to justify the scope of the claims”. The instant specification does not provide direction or any example on a monoclonal antibody encompassed by claim 14 for the early treatment and/or prevention of relapse of GPA.
The specification proposes a new approach for early treating and/or preventing relapse of GPA, but the specification does not show any in vivo data on any treatment regimen of any GPA. All the functional studies were conducted in vitro, as set forth above. Importantly, in the neutralizing assay on the production of ROS, the neutrophils were incubated with 4C3 for 15 minutes and then purified IgG from GPA patients was added. This setting is different from treating a GPA patient, because many GPA patients have high level of PR3-ANCA (anti-PR3 auto-antibodies) which might block binding of 4C3 to PR3.
Furthermore, Amsler (Amsler et al., Rheumatology, 2024, 63, 2249-2258, Publication Date: 11/08/2023) teaches that previous studies have shown that ANCA can activate neutrophils in vitro to generate large amounts of ROS, which are assumed to mediate vascular endothelium damage in vivo. However, there is an ongoing debate as to whether ROS production is paradoxically decreased in GPA patients or if this observed effect is solely due to glucocorticoid treatment. Two older studies have shown that glucocorticoids can influence neutrophil activity and ROS production in AAV and other patients. A more recent study found that neutrophils from treated and untreated patients with active AAV had a decreased capacity to generate ROS. Thus, the activity of inhibiting the production of ROS by neutrophils in vitro may not correlated with therapeutic activity for treating/preventing relapse of GPA.
The quantity of experimentation needed:
As illustrated above, clearly, the art of using antibody in immunotherapy is not a simple matter of visualizing a desired compound, generating a monoclonal antibody, and obtaining a desired therapeutic antibody.
The factors outlined in In Re Wands' mentioned above apply here, and in particular as per the MPEP 2164.01 (a): "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)." It is very clear that one could not make/use this very broad invention that has no working examples in this unpredictable art without undue experimentation. Genetech Inc vs Nova Nordisk 42 USPQ 2d 1001 "A patent is not a hunting license. It is not a reward for search but compensation for its successful conclusion and patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable."
Given the numerous unspecified monoclonal antibodies encompassed by claim 14, the lack of specific guidance and the insufficient in vivo working example, undue experimentation would be required of one of skilled in the art to produce the invention commensurate with the scope of the claims from the instant specification alone.
For all of the above reasons, the claims are properly rejected as lacking enablement for the full scope of compounds encompassed by the claims.
Related Prior Art
Haeberle (US 2016/0228520 A1, Publication Date: 08/11/2016) teaches methods of treating a vasculitic syndrome comprising administering a composition comprising a PR3 inhibitor. The PR3 inhibitor can be a PR3 antibody and the vasculitic syndrome can be granulomatosis with polyangiitis ([0009], claims 1 and 7). The antibody may be a monoclonal antibody ([0046]). The antibody recognizes one or more of Lys99, Ser195, Asp102, and His57 of PR3 (a conformational epitope of PR3) ([0051)). The antibody may be capable of selectively binding to PR3 and inhibiting PR3 interaction with c-ANCA or neutrophil degranulation ([0054]). However, Haeberle does not teach that the monoclonal antibody is capable of inhibiting by at least 30% the production of reactive oxygen derivatives by neutrophils, said production of reactive oxygen derivatives being induced by the presence of autoantibodies directed against PR3. Haeberle does not teach/suggest any PR3 antibody which has claimed properties described in this application, such as being capable of inhibiting by at least 30% the production of reactive oxygen derivatives by neutrophils, said production of reactive oxygen derivatives being induced by the presence of autoantibodies directed against said neutrophil proteinase 3. As set forth above, only antibody 4C3 has the claimed properties. Anti-PR3 antibody 4C3 has many distinct features: 1) 4C3 has distinct epitope (Figs. 4B-4E; and [0299-0302]); 2) 4C3 does not inhibit PR3 enzymatic activity ([0304]); 3) 4C3 leads to an increase in PR3 expression on the surface of neutrophils (Fig. 9 and [0324]); 4) 4C3 is not able to induce Reactive Oxygen Species (ROS) production, thus 4C3 is not an activating antibody (Fig. 10 and [0325]); 5) 4C3 does not induce an increase in CD11b/CD18 surface expression (Fig. 13 and [0326-0328]); 6) 4C3 can inhibit production of ROS induced by ANCA (anti-PR3 auto-antibodies) (Fig. 20 and [0333-0340]). Thus, it would not be obvious that any of Haeberle’s antibodies would have the claimed properties like 4C3.
WO 2012/108650 A2 (Publication Date: 08/16/2012, cited in IDS of 11/21/2022, but in Korean, an English translated version attached in this office action) teaches a monoclonal antibody to PR3 as a therapeutic agent for a stroke (Abstract and 1st sentence of Description on page 2). The PR3 monoclonal antibody can inhibit production of ROS in microglia induced by PR3. However, the ROS production assay was done in different setting: one in microgial and the other in neutrophils (the instant application). In addition, the instant claims require that the PR3 antibody (such as 4C3) can inhibit ROS production induced by other anti-PR3 antibodies (ANCA). Thus, WO 2012/108650 does not teach that the monoclonal antibody is capable of inhibiting by at least 30% the production of reactive oxygen derivatives by neutrophils, said production of reactive oxygen derivatives being induced by the presence of autoantibodies directed against PR3, or early treatment and/or prevention of relapse of granulomatosis with polyangiitis comprising the administration of the pharmaceutical composition comprising the antibody.
Conclusion
No claims are allowed.
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/CHENG LU/ Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/ Supervisory Patent Examiner, Art Unit 1642