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 .
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.
Withdrawn Objections/Rejections
The objections to the specification are withdrawn in response to the amendments.
The objections to the claims are withdrawn in response to the amendments.
The rejection of the claims under 102 and 103 are withdrawn in response to the amendments.
Priority
Acknowledgment is made of the present application as a proper National Stage (371) entry of PCT Application No. PCT/US2020/053090 filed 09/28/2020, which claims benefit under 35 U.S.C. 119(e) to provisional application No. 62/906,709, filed 09/26/2019.
Status of the Claims
Claims 1-2, 4, 6, 9, 11, 15-17, 20, 22, 30, 34-35 and 37-40 are pending; claims 1-2, 4, 6, 9, 15, 20 and 34-35 are amended; claims 3, 5, 7-8, 10, 12-14, 18-19, 21, 23-29, 31-33 and 36 are canceled; claims 37-40 are newly recited, no claims are withdrawn. Claims 1-2, 4, 6, 9, 11, 15-17, 20, 22, 30, 34-35 and 37-40 are examined below.
Claim Rejections - 35 USC § 112
New Rejections
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, 6, 9, 11, 15-17, 20, 22, 30, 34-35 and 37-40 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.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. The specification does not reasonably provide enablement for a first and second model that correlate ADCC activity level of the antibody composition with TAF and AF/HM content, respectively, wherein an assay which directly measures ADCC activity of the antibody composition is not carried out on the antibody composition.
The specification does not provide evidence that the claimed methods of using the models are effective without carrying out an assay which directly measures ADCC activity of the antibody composition. The evidence provided shows that directly measuring ADCC activity of the antibody composition is required when using the models (“ADCC levels for each representative sample of the anti-CD20 antibody was determined by the assay described in Example 2” para. 206, “ADCC levels for each representative sample of the anti-TNFα antibody was determined by the assay described in Example 2” para. 225). Therefore, 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.
MPEP § 2164.01 states:
The standard for determining whether the specification meets the enablement
requirement was cast in the Supreme Court decision of Minerals Separation Ltd. v. Hyde, 242 U.S.261, 270 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? That standard is still the one to be applied.
In re Wands, 858F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term "undue experimentation," it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation.
In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988).
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
In regard to Wands factors (A) and (B), the breadth of the claims needed to enable the invention is determined by whether the scope of enablement provided to one skilled in the art by the disclosure is commensurate with the scope of protection sought in the claims. AK Steel Corp. v. Sollac, 344 F.3d 1234, 1244, 68 USPQ2d 1280, 1287 (Fed. Cir. 2003); In re Moore, 439 F.2d 1232, 1236, 169 USPQ 236, 239 (CCPA 1971). The propriety of a rejection based upon the scope of a claim relative to the scope of the enablement concerns (1) how broad the claim is with respect to the disclosure and (2) whether one skilled in the art could make and use the entire scope of the claimed invention without undue experimentation.
The nature of the invention is a biological/chemical case, where there is natural unpredictability in performance of certain species other than those specifically enumerated; see MPEP § 2163. Accordingly, it is the Office’s position that undue experimentation would be required to practice the claimed method(s), with a reasonable expectation of success, because it would not have been predictable from the disclosure that the claimed models would function as claimed with respect to not measuring ADCC activity of the antibody composition (see MPEP § 2164.03).
In regard to Wands factors (C), (D) and (E), the state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains and provides evidence for the degree of predictability in the art; see MPEP § 2164.05(a).
Accordingly, Schnueriger et al. Molecular Immunology Volume 48, Issues 12–13, July 2011, Pages 1512-1517 https://doi.org/10.1016/j.molimm.2011.04.010 -Cite No. D24 of IDS 7/27/2023 (“Schnueriger”) teaches that “[w]hile ADCC has been studied extensively, measurement of ADCC activity usually relies on primary human PBMCs, with associated donor-to-donor variability caused by differences in immune status and variations in the genetic background (Armour et al., 2010; Breunis et al., 2009; Greenwood et al., 1993; Ljunggren et al., 1987; Metes et al., 2001) and unpublished observation. It has therefore been difficult to measure ADCC activity consistently in a quantitative manner. Here, we report on the development of a cellular in vitro system to measure ADCC of therapeutic antibodies and show data for a humanized IgG1 antibody targeting the CD20 antigen” page 1512 col. 2 para. 1).
Also, Miller et al. Journal of Immunological Methods Volume 385, Issues 1–2, 30 November 2012, Pages 45-50 https://doi.org/10.1016/j.jim.2012.08.004 (“Miller”) teaches that “ADCC activity is typically measured in vitro by mixing antigen expressing target cells with freshly isolated NK cells or peripheral blood mononuclear cells (PBMC) in the presence of increasing concentrations of the mAb of interest (Ljunggren et al., 1987; Nelson et al., 2001; Alter et al., 2004). These assays are critical to the successful development and characterization of therapeutic antibodies that have ADCC as part of their mechanism of action (MoA). However, an ADCC assay may not be available at early stages of therapeutic mAb development due to challenges in obtaining suitable target and/or effector cells” (page 45 col. 2 para. 2). Miller further teaches “Development of an ELISA based bridging assay as a surrogate measure of ADCC” (Title).
Given the cited teachings of the prior art that determining ADCC is difficult and thus requires a direct assay of the antibody composition, the cited references demonstrate that the use of models that require ADCC, without carrying out an assay to measure ADCC, is unpredictable.
While the level of skill in the art is high, the amount of guidance provided regarding how to use the claimed models in the claimed methods, i.e. without assaying ADCC, is scant. Accordingly, the amount of experimentation required to determine how to use the recited models without directly assaying ADCC is quite extensive.
Due to the large quantity of experimentation necessary to determine how to use the recited models without directly assaying ADCC, the lack of direction/guidance presented in the specification regarding the same, the absence of working examples directed to the same, the complex nature of the invention, the limited state of the prior art, the unpredictability of the effects of complex biological molecules on physiological systems, and the breadth of the claims, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention.
In view of all of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention, and thus, the claimed invention does not satisfy the requirements of 35 U.S.C. §112 first paragraph.
Maintained Rejections
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, 6, 9, 11, 15-17, 20, 22, 30 34-35 and 37-40 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.
Independent claim 1 recites “a method of determining product quality of an antibody composition, wherein the ADCC activity level of the antibody composition is a criterion upon which product quality of the antibody composition is based, said method comprising i. determining the total afucosylated (TAF) glycan content of a sample of an antibody composition, ii. determining the product quality of the antibody composition as acceptable and/or achieving the ADCC activity level criterion when the TAF glycan content determined in (i) is within a target range, wherein the target range of TAF glycan content is based on (1) a target range of ADCC activity levels for a reference antibody and (2) a first model which correlates ADCC activity level of the antibody composition to the TAF glycan content of the antibody composition, wherein the ADCC predicted by the first model is about 95% to about 105% of the ADCC predicted by a second model, wherein the second model correlates the ADCC activity level of the antibody composition to the high mannose (HM) glycan content and the afucosylated (AF) glycan content of the antibody composition”. However, even though the claim recites that the “ADCC activity level of the antibody composition is a criterion upon which product quality of the antibody composition is based”, there is no clear use of the ADCC activity level of the antibody and thus the criterion of ADCC activity level in the claim. The method to determine product quality is solely assessed by the TAF glycan content of the antibody composition. Consequently, “wherein the ADCC activity level of the antibody composition is a criterion upon which product quality of the antibody composition is based” is vague thus leading to confusion regarding the scope of the claims.
Furthermore, claim 1 recites the limitation "the level of antibody-dependent cellular cytotoxicity (ADCC)" in line 2. There is insufficient antecedent basis for this limitation in the claim.
The wherein clauses attempt to limit the target range of TAF glycan content “based on (1) a target range of ADCC activity levels for a reference antibody and (2) a first model which correlates ADCC activity level of the antibody composition to the TAF glycan content of the antibody composition…”. But the limitation “based on (1) a target range of ADCC activity levels for a reference antibody” is not clear given that the reference antibody and the method to base the target range of ADCC activity levels of the reference antibody to the target range of TAF glycan content is not recited. A person having ordinary skill in the art would have no way of knowing how the ADCC activity levels of a reference antibody relate to the target range of TAF glycan content. Similarly, limiting the target range of TAF glycan content “based on …(2) a first model which correlates ADCC activity level of the antibody composition to the TAF glycan content of the antibody composition” is also unclear because the claim fails to recite how the ADCC relates to the target range of TAF glycan content. The specification paragraph 6 (page 3) discloses that “[i]n exemplary instance, the first model is any of one of the models (e.g., equations) described herein which correlate ADCC and TAF glycan content, including but not limited to, Equations 1, 3, 5, and 7 and Equation A”. However, none of the equations disclosed teach how the ADCC activity level of the antibody composition and TAF glycan content relate to the target range of TAF glycan content. Therefore, this wherein clause is too vague. A person having ordinary skill in the art would have no way of knowing how the target range of TAF glycan content is determined or calculated such that it may be used as recited..
Furthermore, the term “based on” is not clear. Specifically, it is not clear what is meant by “based on” because “based on” can be interpreted as an inherent property of the target range of TAF glycan content. For example, if the target range is obtainable by any other method, then basing the target range of TAF glycan content on “(1) a target range of ADCC activity levels for a reference antibody and (2) a first model which correlates ADCC activity level of the antibody composition to the TAF glycan content of the antibody composition” does not clearly define the method. A person having ordinary skill in the art would not be able to know exactly how the target range is determined or calculated such that it may be used as recited.
The second wherein clause (last four lines of claim 1), i.e. “wherein the ADCC predicted by the first model is about 95% to about 105% of the ADCC predicted by a second model, wherein the second model correlates the ADCC activity level of the antibody composition to the high mannose (HM) glycan content and the afucosylated (AF) glycan content of the antibody composition”, is unclear. To begin, the specification paragraph 50 discloses that “"total afucosylated glycans" or "TAF glycans" refers to the sum amount of high mannose (HM) glycans and afucosylated glycans”, i.e. TAF = HM + AF. Therefore, given that both the first and the second model use the TAF glycan content of the antibody composition (the second model using HM + AF, and the first model using TAF) and the ADCC activity level of the same antibody composition, both models are effectively the same. It is not clear whether the second wherein clause imparts any limitation given that both models are equivalent, both models using the exact same input values (ADCC activity level of the antibody composition correlated to the TAF glycan content of the antibody composition). The second wherein clause is also unclear because the claim fails to recite how the ADCC relates to the target range of TAF glycan content. The specification paragraph 6 (page 3) discloses that “[i]n exemplary instance, the second model is any of one of the models (e.g., equations) described herein which correlate ADCC and HM glycan content and TAF glycan content, including but not limited to, Equations 2, 4, 6, and 8 and Equation B”. However, none of the equations disclosed teach how the ADCC activity level of the antibody composition and HM glycan and AF glycan content relate to the target range of TAF glycan content. Therefore, this wherein clause is vague. A person having ordinary skill in the art would have no way of knowing how the target range of TAF glycan content is determined or calculated such that it may be used as recited.
The terms “HM”, “AF” and “TAF” are unclear, further contributing to the indefiniteness of the claims. The specification paragraph 50 discloses that ““AF glycan”” refers to glycans which lack a core fucose”. Therefore, under the broadest reasonable interpretation, AF glycans encompass HM glycans given that HM glycans are “glycans comprising 5, 6, 7, 8, or 9 mannose residues” (specification paragraph 50). Similarly, HM glycans would comprise AF glycans given the definition of HM. This means that the term TAF recited in claim 1 is unclear because TAF = HM + AF, therefore it is not clear whether the species of AF and HM are counted twice or just once and if they belong as an HM or an AF. Similarly, it is not clear how a person having ordinary skill in the art would apply the TAF, HM and AF content to determine target range of TAF glycan content and product quality.
Claims 37 recites “…b) determining the total afucosylated (TAF) glycan content of a sample taken from the cell culture to calculate the ADCC activity level using a first model…”. Claim 39 recites “b. determining the total afucosylated (TAF) glycan content of a first sample taken from the cell culture at a first timepoint to calculate the ADCC activity level using a first model, c. determining the TAF glycan content of a second sample taken from the cell culture at a second timepoint which is different from the first timepoint to calculate the ADCC activity level using the first model”. However, it is not clear how the determination of TAF glycan content is used to calculate the ADCC activity level using a first model. For example, “the ADCC” lacks antecedent basis. A person having ordinary skill in the art would not be able to recognize what is being claimed by “the ADCC activity level” because a ADCC is not previously recited.
Claim 37 further recites “c) collecting the antibody from the cell culture, when the ADCC activity level is within a target range of ADCC activity levels for a reference antibody”. However, this step is also unclear because the claim fails to recite a target range of ADCC or the reference antibody. Therefore, a person having ordinary skill in the art would have no way of knowing when to collect the antibody from the cell culture.
Similarly to claim 1, claims 37 and 39 further recite “wherein the first model correlates ADCC activity level of the antibody composition to the TAF glycan content of the antibody composition and the ADCC activity level predicted by the first model is about 95% to about 105% of the ADCC activity level predicted by a second model, wherein the second model correlates the ADCC activity level of the antibody composition to the high mannose (HM) glycan content and the afucosylated (AF) glycan content of the antibody composition”. As discussed above, the first and second model appear to be analogous given that both correlate ADCC activity level to TAF or (HM + AF = TAF) and therefore these clauses also appear to fail to impart any limitations to the claims.
Claims 2, 4, 6, 9, 11, 15-17, 20, 22, 30, 34-35, 38 and 40 are included in this rejection because they depend from rejected claims 1, 37 or 39 but fail to clarify the scope of patent protection sought.
Response to Arguments
Applicant's arguments filed 1/26/2026 have been fully considered but they are not persuasive.
Regarding the rejection of claim 1 under 112b,
Applicant argues that “The skilled person would understand the meaning of the phrase "wherein the ADCC activity level of the antibody composition is a criterion upon which product quality of the antibody composition is based" in the context of the claim, the application, and in view of the teachings of, e.g., Reusch and Tejada, Glycobiology 25(12) 1325-1334 (2015)” (page 10 para. 3)
However, “wherein the ADCC activity level of the antibody composition is a criterion upon which product quality of the antibody composition is based” is unclear because the method does not recite an active step of measuring ADCC (see rejection above). The teachings of Reusch and Tejada, i.e. that antibody compositions elicit ADCC, does not clarify the issues with the claim.
Applicant further argues that “ADCC activity level is not directly measured and therefore, there is no "use of ADCC activity level". The Office Action at page 5, lines 3-4, stating that "the method to determine product quality is solely assessed by the TAF glycan content of the antibody composition" suggests that claim 1 is in fact clear, since product quality of the antibody composition is assessed upon determination of the TAF glycan content of the antibody composition, not through measurement of the ADCC activity level” (page 10 para. 5).
However, contrary to Applicant’s remark, the method to determine product quality being solely assessed by the TAF glycan content of the antibody composition suggests that the ADCC is not a criterion upon which product quality of the antibody composition is based, thereby rendering the claim indefinite.
Applicant further argues that “paragraph 0045 makes it clear that high mannose glycans consist of two N-acetylglucosamine moieties and a large number (e.g., 5, 6, 7, 8 or 9) of mannose (Man) residues” (page 12 para. 1).
However, although paragraph 0045 makes it clear that high mannose glycans consist of two N-acetylglucosamine moieties and a large number (e.g., 5, 6, 7, 8 or 9) of mannose (Man) residues; given that the specification paragraph 50 discloses that ““AF glycan”” refers to glycans which lack a core fucose”, under the broadest reasonable interpretation, AF glycans encompass HM glycans, i.e. HM glycans which lack a core fucose would be categorized as both AF and HM. This overlap in scope between AF and HM renders the claims indefinite (see rejection above).
Applicant further argues that “From these teachings, one of ordinary skill in the art would understand that the target range of TAF glycan content is established by using the known or pre-determined ADCC activity levels for the reference antibody as input into the first model to calculate the TAF glycan content target range” (page 13 para. 5)
However, given that the claims fail to recite the reference antibody, the known or pre-determined ADCC activity levels of the reference antibody or how the models are used to base the target range of TAF glycan content, the claims remain rejected under 112b (see rejection above for the complete analysis).
Applicant further argues that “Mathematically speaking, if ADCC activity
level is 30 multiplied by the% TAF glycan level, then, by the assumption of the Office Action, ADCC activity level is 30*(HM+AF) or 30HM+30AF. This is, however, not true. In some instances, HM impacts ADCC activity levels to a greater extent than the impact by AF, while in other instances the converse is true. Specific model equations described in the application exemplify this concept” (page 14 paras. 1-2).
However, contrary to Applicant’s argument, mathematically speaking, if ADCC activity level is 30 multiplied by the% TAF glycan level, then, ADCC activity level is 30*(HM+AF) or 30HM+30AF. This would be true after substituting the appropriate values for HM and AF into the equation. In other words, the fact that in some instance HM impacts ADCC activity levels to a greater extent than the impact by AF, while in other instances the converse is true, does not provide evidence that the first and the second models are, under the broadest reasonable interpretation, the same (see rejection above).
Applicant further argues that “the second model is not purposed for connecting ADCC and HM glycan content and AF glycan content to the target range of the TAF glycan content” (page 16 para. 2).
However, the second model is used for determining the target range of TAF, albeit, by its relation to the first model. Nevertheless, the second model does not clarify or otherwise provide the method of basing the target range of TAF glycan content (see rejection above).
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Fernando Ivich/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678