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 .
The amendment to the claims filed on 03/13/2026, does not comply with the requirements of 37 CFR 1.121(c) because deleted text in claim 13 (parts b and c where deleted recitations of optionally are not properly annotated) is not annotated by strikethrough or double brackets. While reasonable efforts to identify all instances of noncompliance have been made, Applicant’s assistance in identifying and correcting any additional or further instances is greatly appreciated. Amendments to the claims filed on or after July 30, 2003 must comply with 37 CFR 1.121(c) which states:
(c) Claims. Amendments to a claim must be made by rewriting the entire claim with all changes (e.g., additions and deletions) as indicated in this subsection, except when the claim is being canceled. Each amendment document that includes a change to an existing claim, cancellation of an existing claim or addition of a new claim, must include a complete listing of all claims ever presented, including the text of all pending and withdrawn claims, in the application. The claim listing, including the text of the claims, in the amendment document will serve to replace all prior versions of the claims, in the application. In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered).
(1) Claim listing. All of the claims presented in a claim listing shall be presented in ascending numerical order. Consecutive claims having the same status of “canceled” or “not entered” may be aggregated into one statement (e.g., Claims 1–5 (canceled)). The claim listing shall commence on a separate sheet of the amendment document and the sheet(s) that contain the text of any part of the claims shall not contain any other part of the amendment.
(2) When claim text with markings is required. All claims being currently amended in an amendment paper shall be presented in the claim listing, indicate a status of “currently amended,” and be submitted with markings to indicate the changes that have been made relative to the immediate prior version of the claims. The text of any added subject matter must be shown by underlining the added text. The text of any deleted matter must be shown by strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters. The text of any deleted subject matter must be shown by being placed within double brackets if strike-through cannot be easily perceived. Only claims having the status of “currently amended,” or “withdrawn” if also being amended, shall include markings. If a withdrawn claim is currently amended, its status in the claim listing may be identified as “withdrawn—currently amended.”
(3) When claim text in clean version is required. The text of all pending claims not being currently amended shall be presented in the claim listing in clean version, i.e., without any markings in the presentation of text. The presentation of a clean version of any claim having the status of “original,” “withdrawn” or “previously presented” will constitute an assertion that it has not been changed relative to the immediate prior version, except to omit markings that may have been present in the immediate prior version of the claims of the status of “withdrawn” or “previously presented.” Any claim added by amendment must be indicated with the status of “new” and presented in clean version, i.e., without any underlining.
(4) When claim text shall not be presented; canceling a claim.
(i) No claim text shall be presented for any claim in the claim listing with the status of “canceled” or “not entered.”
(ii) Cancellation of a claim shall be effected by an instruction to cancel a particular claim number. Identifying the status of a claim in the claim listing as “canceled” will constitute an instruction to cancel the claim.
(5) Reinstatement of previously canceled claim. A claim which was previously canceled may be reinstated only by adding the claim as a “new” claim with a new claim number.
As noted above, the amendment under consideration herein fails to comply with 37 CFR 1.121 because the claim listing fails to appropriately reflect cancelled/deleted text. The amendment could be therefore considered non-responsive. In the interest of compact prosecution, the amendment at issue will not be considered non-responsive, however, any future responses failing to comply with 37 CFR 1.121 will be held non-responsive and will not be considered.
Claims 2, 11, and 15-16 are cancelled.
Claim 17 is new.
Claims 1, 3-10, 12-14, and 17 are pending and under examination on the merits.
Priority
This application is a 371 of PCT/US2021/049370, filed 09/08/2021, which claims benefit of priority to US Provisional Application No. 63/076,079, filed 09/09/2020, and US Provisional Applications No. 63/114,949, filed 11/17/2020.
IDS
The Information Disclosure Statement (IDS) filed on 03/13/2026 has been considered.
Maintained-Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Withdrawn Objections and Rejections
The objections to the specification are withdrawn in light of the corrective amendments dated 03/13/2026. The objections to claims 1, 5, 10, 14, and 15 are withdrawn in light of the corrective claim amendments dated 03/13/2026. The objections and rejections of claims 2 and 11 are withdrawn as moot in light of the cancellations of claims 2 and 11 resulting from the claim amendments dated 03/13/2026. The rejection of claim 5 for the recitation of ‘the nucleus’ without antecedent basis is withdrawn upon further consideration of the artisan’s ability to discern what is meant in light of inherency without antecedent basis. The rejections under 35 USC §112(b) to claims 6 and 12 are withdrawn in light of the corrective claim amendments dated 03/13/2026. The rejections under 35 USC §112(b) to claims to claims 12-13 for recited staining of intensities a 1+, 2, 3, etc. are withdrawn upon further consideration of the state of the art. The rejections of the claims under §103 and for double patenting as presented in the previous office action dated 12/17/2025 are withdrawn and replaced with the rejections presented in this Office Action to better account for the new claim scope resulting from the claim amendments dated 03/13/2026.
New-Claim interpretation
The recitation of ‘a portion’ in lines 2 and 4 of step c of claim 1 are interpreted to refer to the same portion (sample and sample size).
All recitations of “complete nuclear staining” are being interpreted to be consistent with the only description of complete or incomplete staining in the disclosure (lines 10-19 of page 37 of the specification) such that complete nuclear staining occurs when entirety of the chromatin is stained which occurs when the staining intensity is greater than or equal to 1 intensity. No other definition is described or supported in the instant disclosure or is supplied as agreed upon in the prior art.
New-Claim Objections
Claim 1 is objected to because of the following informalities: “Ki~67” in line 1 of step b should read “Ki-67”.
Claim 17 is objected to because of the following informalities: “the anti-Ki-67” in line 2 and “ or the anti-Ki-67” in line 3 should read “the anti-Ki-67 antibody” and “or the anti-Ki-67 antibody”, respectively.
Appropriate correction is required.
Maintained-Claim Rejections - 35 USC § 112
35 USC § 112(a)
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.
Written Description
Claims 1, 3-10, and 12-15 remain rejected and newly added claim 17 is 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.
The purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B. V. v. Dianwnd Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
The Application claims a broad genus of antibodies without any required complementarity determining region (CDR) structure/sequences (where the artisan would understand that the CDR1-6 structure/sequences are the minimal part of the antibody that is responsible for/dictates binding of the antibody to its target) without disclosure of a conserved structure/representative number of species to adequately describe said genus. The Application discloses a single species of commercially available antibody known to bind Ki-67 (see for example, page 3 of the instant specification). Therefore, in view of this disclosure, Applicant is claiming a broad genus of antibodies, including as of yet undiscovered antibodies, without a representative number of species of said genus. The specification does not provide adequate written description for the entire claimed genus of species of antibodies or of CDRs capable of binding Ki-67 as claimed, because in the absence of empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically, which light and heavy chain CDR sequence combinations (bearing any mutations or not) might be included in the 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 Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. 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. Applicant has only fully disclosed 1 species for consideration. Thus, given the substantial antibody structure variation within the genus as well as the high level of unpredictability in the art, the disclosure of only 1 species having 100% homology is not sufficiently representative of the entire genus claimed (encompassing CDRs not described or even invented and/or multiple combinations of mutations in the CDRs).
Furthermore, Applicant has not disclosed relevant, identifying characteristics of CDR region amino acid sequences that confer upon an antibody the ability to function as claimed because the instant specification does not provide structural antibody features that correlate with a functional ability to function.
Absent a clear description of the at least minimal structural features correlating with a functional ability to function as claimed which are shared by members of a genus commonly sharing this function, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish which heavy and light chain CDR amino acid sequences may be mutated/varied/interchanged such that the resultant heavy and light chain variable regions comprise six CDRs that confer the ability to function as claimed.
Furthermore, while the prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains. For example, Al Qaraghuli et al (2020, Nature Scientific Reports 10:13969), state that the six CDRs form a continuous surface to form the paratope that binds the epitope of the cognate antigen. This suggests that a change in the CDR sequence may result in a conformationally different paratope which may fail to bind target as claimed. Here, a mutation in the CDRs may result in a paratope unable to bind Ki-67. Rabia, et al (2018, Biochemical Engineering Journal 137:365-374) teach what effects mutations can have on an antibody's stability, solubility, binding affinity and binding specificity. Rabia et al report that an increase in antibody affinity can be associated with a decrease in stability (p. 366, col. 2 last paragraph; Fig. 2). Tiller et al (2017, J. Biol. Chem. (2017) 292(40) 16638–16652) and Tsuji et al (2022, J Virol 96:e00071-22) teach that mutations in the CDRs (especially HCDR3 are unpredictable and accompanied by tradeoffs in performance (for example increased affinity may lead to decreased specificity); see references in their entirety paying particular attention to the abstract of Tiller et al and the abstract and results section of Tsuji et al). The above cited references underscore the unpredictability of even a single mutation in the CDRs. The instant claims allow for mutations in the CDRs whereupon the mutated paratope may fail to bind Ki-67, as claimed. Thus, the claims need to specify exact CDR sequences of the anti-Ki-67 antibody.
Accordingly, absent empirical determination, one skilled in the art would be unable to predict or envision which CDR sequences comprised within the genus comprising the claimed CDR sequences may be combined/mutated such that the resultant antibody possesses an antigen-binding site capable functioning as claimed. The general knowledge and level of skill in the art does not adequately supplement the omitted description, because specific, not general guidance is needed. Since the disclosure fails to describe relevant, identifying structural characteristics, in the form of fixed heavy and light chain CDR amino acid sequence combinations, that correlate with the ability to function as claimed, and because the one disclosed species detailed above is not sufficient to describe the claimed genus, it is submitted that the written description requirement of 35 U.S.C. 112(a) has not been met.
The claims require an antibody capable of binding Ki-67. The specification does not describe which amino acid residues of the antibody are responsible for the functions claimed. Rather, the specification implies that these potential agents must first be screened in an assay to ascertain if the agents have the functions required by the instant claims. Although the specification provides disclosure of 1 antibody, it fails to disclose the structures common to all members of the genus of antibodies encompassed by the broad definition provided by applicant. The specification does not disclose the structure of all of the claimed variant antibodies and fails to disclose which sequences are responsible for the functions claimed. In the absence of a known or disclosed correlation between structure and function, claims which encompass variants defined by their function are generally not considered described.
Applicant is directed to MPEP § 2163 for guidelines on compliance with the written description requirement. Here, applicant has not described a reasonable number of members of the genus of antibodies that would function in the method(s) as claimed, but rather has presented the public with an idea of how to perform an assay that might identify some peptides that fall within the scope of the claim. Of course, depending on what agents are used in the screening assay, it may well identify none. The Court of Appeals for the Federal Circuit addressed claims of this sort in great detail in University of Rochester v. G.D. Searle and Co. (69 USPQ 2nd 1886, CAFC 2004). In Rochester, the Federal Circuit upheld the district court's ruling that patent claims which recited administration of compounds not disclosed, but rather to be identified in a screening assay, were invalid on their face.
In Ariad, the court further noted that the written description plays a particularly important role in the biological arts, where patentees might otherwise be tempted to claim a genus of compounds by its function or result:
“The written description requirement also ensures that when a patent claims a genus by its function or result, the specification recites sufficient materials to accomplish that function—a problem that is particularly acute in the biological arts. 5 See Guidelines for Examination of Patent Applications Under the 35 U.S.C. 112, 1, “Written Description” Requirement, 66 Fed. Reg. 1099, 1105-1106 (Jan. 5, 2001). This situation arose not only in Eli Lilly but again in University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916 [69 USPQ2d 1886] (Fed. Cir. 2004). In Rochester, we held invalid claims directed to a method of selectively inhibiting the COX-2 enzyme by administering a non-steroidal compound that selectively inhibits the COX-2 enzyme. Id. at 918. We reasoned that because the specification did not describe any specific compound capable of performing the claimed method and the skilled artisan would not be able to identify any such compound based on the specification's function description, the specification did not provide an adequate written description of the claimed invention. Id. at 927-28. Such claims merely recite a description of the problem to be solved while claiming all solutions to it and, as in Eli Lilly and Ariad's claims, cover any compound later actually invented and determined to fall within the claim's functional boundaries—leaving it to the pharmaceutical industry to complete an unfinished invention.”
Ariad Pharmaceuticals., Inc. v. Eli Lilly & Co., 94 USPQ2d 1161, 1173 (Fed. Cir. 2010) (en banc). Emphasis added.
The Federal Circuit has clarified Written Description as it applies to antibodies in the recent decision Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. 112(a) (or pre-AIA first paragraph) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called “newly characterized antigen” test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the “newly characterized antigen” test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad, 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of an antigen alone is not considered adequate written description of a claimed antibody to that antigen, even when preparation of such an antibody is routine and conventional. Id.
While generically the structure of antibodies is known, the structure of the presently recited antibodies can vary substantially within the above given claimed recitations. As noted in Amgen, knowledge that an antibody binds to a particular epitope on an antigen tells one nothing at all about the structure of the antibody, wherein “instead of analogizing the antibody-antigen relationship to a ‘key in a lock,’ it [is] more apt to analogize it to a lock and ‘a ring with a million keys on it.” (Internal citations omitted). The relevant antibody art confirms this quandary, indicating that “knowledge of an epitope or antigen used to generate a monoclonal antibody is insufficient for making the original antibody available, even if suitable in vitro test systems for screening are used.” See p. 8, lines 3-5 of WO 2009/033743 A1. Therefore, those of skill in the art would not accept that the inventor had been in possession of the full genus of antibodies in the present claims.
Although screening techniques can be used to isolate CDR variant antibodies that possess the ability to function as claimed, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the 'written description' requirement is broader than to merely explain how to 'make and use'; the applicant must also convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed.”
Therefore, the antibodies, as claimed are only disclosed by function/insufficient structure, without a representative number of species or unifying, conserved structure clearly enabling one skilled in the art to readily envisage the members of the genus claimed which would function as claimed in the claimed method(s). Therefore, claims 1, 3-10, 12-15, and 17 are deemed to fail to meet the written description requirement, as presently drafted.
Enablement
Claims 8-9 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while teaching that Ki-67 is expressed in certain cancers/tumors (see for example, Table 3 at pages 26-28 of the instant specification) and while providing enablement for embodiments/recitations not pertaining to administration of a cancer therapeutic based upon a Ki-67 score (recitations of determining and scoring according to claim 1 using the cell populations of claims 8 and 9), does not reasonably provide enablement for treating a cancer or tumor comprising administering a cancer therapeutic based on the Ki-67 score obtained from the claimed methods. 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 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.
MPEP 2164.01(a) states that in order to determine compliance with the enablement requirement, the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is “reasonable” or 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.
The breadth of the claims
Claims 8-9 are broadly directed to embodiments comprising determining likelihood of response to a cancer therapeutic or administering a cancer therapeutic and secondary treatment based upon a determined Ki-67 score. Note that cancer is a broad genus of heterogenous diseases. The claims are effectively drawn to/encompass a method(s) for treating cancer/tumor types comprising administering a therapeutic based upon a determined Ki-67 score (%). The encompassed cancers/tumor types are considered broad because they are characterized by involvement of different cell types, location, and microenvironmental conditions.
The nature of the invention
Claims 8-9 are broadly directed to embodiments comprising determining likelihood of response to a cancer therapeutic or administering a cancer therapeutic and secondary treatment based upon a determined Ki-67 score. The claims are directed to biological subject matter which is understood to be complex and often unpredictable.
The state of the prior art
The state of the prior art supports that cancer is a highly heterogenous disease (as evidenced by Allison et al, (Heterogeneity and Cancer, retrieved from: https://www.cancernetwork.com/view/heterogeneity-and-cancer (2014); at paragraph 1 of the Introduction)) and there is no reasonable expectation to expect administration of a therapeutic based upon Ki-67 scoring to function therapeutically in all of the encompassed cancers/tumor types (as evidenced by American Cancer Society (Can Cancer be Cured?, American Cancer Society, retrieved from: https://www.cancer.org/cancer/understanding-cancer/can-cancer-be-cured.html)(2021)).
The level of one of ordinary skill
As the claims are directed to methods involving treatment of cancer, the artisan is presumed to be highly skilled, tending to have an advanced degree (such as a Ph.D. or an M.D.).
The level of predictability in the art
Given Allison et al and American Cancer Society teaching the heterogeneity of cancers/tumor types and their treatments, the cited references demonstrate that the characterization, pathology, and treatment of different cancers are unpredictable.
(F) The amount of direction provided by the inventor
The instant specification mentions administration 15 times at a high level of generality (untied to any particular cancer and unlinked to a reasonable expectation of success using any treatment or therapeutic administered based on a Ki-67 score (%)). Therefore, the guidance effectively amounts to a mere suggestion to try to develop such a method where Ki-67 may be a promising, but as of yet unvalidated guide post for such downstream administration steps.
The existence of working examples
There are no working example provided in the instant disclosure that clearly demonstrate using a Ki-67 score to predict, guide, or implement administration of a cancer therapeutic or treatment. The closest examples would be examples 2 and 5 (beginning at pages 41 and 45, respectively, of the instant specification neither of which demonstrate successful prediction, guiding, or implementation of administration of a cancer therapeutic or treatment based upon a Ki-67 score (%) and both of which are limited to breast cancer.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
The case is directed to biological subject matter, which is by nature complex. There are no working example provided and the state of the art fails to step in to provide enablement where the instant disclosure is lacking. The artisan would be forced into burdensome experimentation so as to effectively invent what applicant only suggests may be possible.
Thus, in light of the contradictory findings in the prior art, discovery of a correlation alone is not enabling for a method using a Ki-67 score (%) to prognose/guide/or implement administration of a therapeutic agent or treatment, even where the agent is narrowed to an ATP competitive inhibitor of a cyclin-dependent kinase such as abemaciclib, or where the cancer therapeutic is narrowed to palbociclib or ribociclib, for cancer in light of the lack of examples or guidance enabling administration of such an agent based upon a Ki-67 score/percent for all cancers.
Matinained-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 4-5, 8-10, and 13-15 remain 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 5 recites the limitation " …the entire chromatin distribution…" in lines 4-5. There is insufficient antecedent basis for this limitation in the claim.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
Regarding claim 4, the claim recites the broad recitation “20 or above”, and the claim also recites “10 or above” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Regarding claim 8, the claim recites the broad recitation “200 cells” and the claim also recites “100 cells” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Regarding claim 9, the claim recites the broad recitation “50% or any about number between 1% and 50%,” and the claim also recites “about 1%, about 5%, about 10%, about 20%, about 30% , about 40%, about 50%...”which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Regarding claim 13, the claim recites the broad recitation “…a monoclonal mouse anti-Ki-67 antibody…,” and the claim also recites “…optionally the anti-Ki-67 comprises monoclonal mouse anti-Ki-67 clone MIB-1, or the anti-Ki-67 comprises a substantially isolated or substantially purified monoclonal mouse anti-Ki-67 clone MIB-1...”which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Unless specifically stated or obvious from context, as used herein, the term
The term “about” in claims 9, 10, and 13 is a relative term which renders the claims indefinite. The instant specification provides that “…’about’ is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About (use of the term "about") can be understood as within 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%,7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.01% of the stated value. Unless otherwise clear from the context, all numerical values provided herein are modified by the term ‘about,’” (see for example, pages 14-15 of the instant specification). The term “about” is not defined by the claim(s), the specification does not provide a closed/limiting, standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear what degree is required/encompassed by the terms modified by the term ‘about.’
The term “unequivocally” in claim 13 is a relative term which renders the claims indefinite. The term “unequivocally” is not defined by the claim(s), the specification does not provide a closed/limiting, standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear what degree is required/encompassed by the terms modified by the term “unequivocally.”
The term “substantially isolated” in claim 13 is a relative term which renders the claims indefinite. The term “substantially isolated” is not defined by the claim(s), the specification does not provide a closed/limiting, standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear what degree is required/encompassed by the terms modified by the term “substantially isolated.”
The term “substantially purified” in claim 13 is a relative term which renders the claims indefinite. The term “substantially purified” is not defined by the claim(s), the specification does not provide a closed/limiting, standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear what degree is required/encompassed by the terms modified by the term “substantially purified.”
The term “defined threshold” in claim 15 has no clear and closed definition provided in the instant disclosure which renders the claim indefinite. The term is not defined by the claim(s), the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The specification states that the threshold may optionally be 1%-50% (see for example, page 8 of the instant specification), however, this definition is not closed and invites the question of whether other values may also be encompassed within the recitation of a defined threshold.
Regarding claim 14, a kit cannot comprise a method. The present drafting leaves unclear what is intended to be required by the metes and bounds of the kit of claim 14. For example, do the guidelines recite the steps of claim 1 or is some other guidance to accomplish the goals of claim 1 sufficient.
New-35 USC § 112(d)
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 5 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 5 appears to merely reiterate in different verbiage the complete nuclear staining which is recited in claim 1 (see the new claim interpretation section), from which claim 5 depends without appearing to narrow the scope of independent claim 1 (and could be argued to broaden the scope of claim 1 by allowing for embodiments with any degree (such as incomplete) nuclear staining). 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 12 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 12 fails to recite a further or more narrow limitation beyond the scope of claim 1 from which it depends. 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.
New-Claim Rejections - 35 USC § 103
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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 3-10, 12-15, and 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Abubakar et al (Breast Cancer Res. 2016 Oct 18;18(1):104. doi: 10.1186/s13058-016-0765-6) in view of Dako (FDA SSED for PD-L1 HC 22C3 pharmDx, obtained from: https://www.accessdata.fda.gov/cdrh_docs/pdf15/P150013S016B.pdf, (FDA approval on 07/30/2019) (Proof of availability further supported by the Google screen capture)), Skjulsvik et al (Int J Clin Exp Pathol. 2014 Dec 1;7(12):8905-10), and Rizzardi et al (Diagn Pathol 7, 42 (2012). https://doi.org/10.1186/1746-1596-7-42).
Regarding claims 1, 12, and 15, instant claims 1 and 15 appear to differ in scope only in so far as claim 15 pertains to invasive tumors and whether the staining is required explicitly to be 1+ of is above a ‘defined threshold’, where otherwise, the reagents, active steps, mathematical formula and mental steps are the same. Abubakar et al teach the International Ki-67 in Breast Cancer Working Group published recommendations aimed at the standardization of the analytical processes for Ki-67 evaluation. Aiming for said standardization, Abubakar et al used tissue microarrays containing tumour tissue cores from breast cancer patients. Staining was accomplished using a Dako autostainer and a standard protocol with Dako MIB-1 antibody diluted 1/50 and visualized using the Dako REAL kit (K5001) [Note that the MIB-1 antibody is also used as an anti-Ki-67 antibody by Applicant (see for example, lines 3-6 of page 3 of the instant specification) (see also, for example, the abstract’s method section at page 1, column 1 of page 2, and column 2 (at the KI67 immunostaining section) of page 3 of Abubakar et al)]. Note that this teaching is deemed to teach contacting the sample with the antibody binding Ki-67. Abubakar et al teach and suggest predictability for using Ki-67 staining in invasive tumor TMAs by teaching that an excellent correlation was observed between Ki-67 staining in TMAs and whole sections (teaching both the desirability of examining Ki-67 and the use of the method of Abubakar et al for such examination with a reasonable expectation of success) (see for example, column 2 of page 10). Abubakar et al teach that there are various means known in the art for scoring Ki-67 (by hand scoring by a pathologist and automated scoring-both of which were used by Abubakar et al (see for example, column 1 of page 3)). Abubakar et al teach scoring to achieve/quantify a % Ki-67 (see for example, Figure 1 and its caption at page 3). Abubakar et al do not appear to teach whether the positive and negative Ki-67 scoring accounted for distribution of staining in the chromatin (complete nuclear staining, see the claim interpretation section above and page 37 of the instant specification). However, it is noted that the instant specification, at the only point where incomplete and (by implied distinction) complete nuclear staining are discussed, discloses that so long as the staining has an intensity greater than or equal to 1, the cell should be included in the numerator, even if incomplete in appearance. Therefore, so long as the intensity of the cells is at an intensity of 1 or greater, the instant disclosure only provides and supports that the cells are then included in the numerator as Ki67+ cells. Thus, any art teaching that the cells are stained or counted positive at an intensity of 1 or more and/or teaching homogenous Ki-67 staining (reading on complete nuclear staining) may make obvious the instantly recited limitation of complete nuclear staining. Note that the phrase “defined threshold” is recited once throughout the instant specification. The only definition of a threshold provided throughout the instant disclosure is the open definitive disclosure that the threshold may optionally be 1%-50% (see for example, page 8 of the instant specification). The Examiner, in the interest of advancing prosecution, continues to interpret the recited defined threshold to be anything at or above 1% staining (which is so low, that it is considered an obvious variant of binary positive/negative staining). Likewise, the Examiner is interpreting the threshold to be any degree of positive Ki-67 staining (as 1% positive staining would appear to yield the same, predictable result as a binary positive/negative cutoff absent evidence to the contrary). Abubakar et al further teach that color (DAB-brown) was selected with respect to intensity representative of the positive and negative nuclear classes (see for example, page 4), noting that Abubakar et al are deemed to teach that staining occurred at an intensity above a defined threshold indicating a positive result because intensity was examined with respect to the determination of positive expression where cells were found to be positive for Ki-67 expression (see for example, page 4).
Abubakar et al do not teach that the Ki-67 scoring includes dividing the number of Ki-67 staining viable tumor or cancer cells specifically bound by the antibody by the total number of staining and non-staining viable cancer or tumor cells and multiplying the result by 100, thereby obtaining the Ki-67 score (%).
However, Dako teaches that PD-L1 protein expression in gastric or GEJ adenocarcinoma, ESCC, cervical cancer, urothelial carcinoma and HNSCC is determined by using Combined Positive Score (CPS), which is the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100.
Note that Dako teaches diagnostic significance of 1% combined positive staining (CPS, which is the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100) for 4 out of 5 cancers investigated (see for example, pages 2 and 6).
Note that while Dako et al teach various defined thresholds (cutoffs) for the different investigated cancers, the artisan would have found it obvious to use any of the defined cutoffs/thresholds of Dako et al or even the suggested cutoff of 1% biomarker (PD-L1) positivity as a lower threshold for initial Ki-67 expression standardization (see for example, pages 2, 6, and 9-11).
Abubakar et al and Dako do not explicitly teach that the intensity of staining is 1+ for positively stained cells.
However, Skjulsvik et al teach, as part of a discussion of Ki-67 immunostaining, that because expression of the Ki-67 antigen changes during the cell cycle, the intensity of nuclear staining will vary; principally, all types of staining should be regarded as positive (see for example, column 2 of page 8908 (noting that robust nature of Ki-67 staining with MIB-1 is discussed in column 1 of page 8908 and the observed homogenous distribution of Ki-67 throughout tumor tissue (see column 2 of page 8907))).
Abubakar et al, Dako, and Skjulsvik et al do not teach that IHC expression scoring is conducted on a scale of 1+ or higher.
However, Rizzardi et al teach that, traditionally, pathologists have visually scored IHC data. For example, in the calculation of an HSCORE, a summation of the percentage of area stained at each intensity level multiplied by the weighted intensity (e.g., 1, 2, or 3; where 0 is no staining, 1 is weak staining, 2 is moderate staining and 3 is strong staining) of staining is generated. These analyses are frequently performed on specimens arrayed on stained TMA sections allowing representation of a sufficiently large number of specimens for statistically rigorous testing. Tissue specimens are adequately represented by tissue cores on very few slides minimizing IHC cost and tissue usage, and facilitating intra-observer, inter-observer and inter-laboratory studies (see for example, column 1 of page 2).
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined prior art references. The artisan would have been motivated to make and use the invention as claimed because Abubakar et al teach desirability of standardizing scoring of Ki-67 expression for diagnosis/treatment of breast cancer and teach means for said standardization. The artisan, understanding that there are multiple means for mathematically standardizing and reporting biomarker expression data would have found it obvious to use any means known in the art for said quantification. The artisan would have been guided to use the method taught by Dako because both Dako and Abubakar et al are concerned with quantitatively reporting biomarker expression data from cancer samples (where Abubakar et al teaches use of the Dako autostainer, suggesting to the artisan the desirability of looking to Dako and Dako’s autostainer publications to find methods for analyzing staining results regardless of the biomarker being examined, understanding that the autostainer and mathematics are not biomarker specific. Abubakar et al and Dako teach examination of staining intensity (see for example, page 2 of Dako and page 4 of Abubakar et al), but neither explicitly teaches a scoring system including a grade of 1+ or that a score of 1+ or higher is considered positively stained for Ki-67. The artisan, looking to Dako, would have been guided to use 1% staining as a relevant and lower end threshold for initial investigation of the relationship of Ki-67 expression and a given cancer/tumor/application of interest. This is underscored where Rizzardi et al, concerned with scoring of intensity for biomarkers in histological samples teaches that scoring on a scale of 1+-3+ is traditionally used in the art, where 0 is traditionally used to indicate a negative result and 1+ indicates weak staining/expression of the biomarker of interest, further guiding the artisan to view an intensity or 1or greater as indicating that the cell is Ki-67 positive for inclusion in the numerator and Skjulsvik et al teach that, with respect to Ki-67 nuclear staining, any staining should be regarded as positive, but notes with particularity that homogenous distribution was observed in tumor tissue samples (see for example, pages 8907-8908 of Skjulsvik et al as well as the rejection of this claim above). The artisan would have found it obvious to use art known means of scoring intensity, such as the method taught by Abubakar et al and Dako through the scoring means of Rizzardi et al and the indications of positive/negative expression staining for Ki-67 as taught by Skjulsvik et al for prognostic purposes (see for example, the abstract of Abubakar et al at page 1). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 3, the combined prior art references teach and make obvious instant claim 1 wherein the cancer or tumor cells are breast cancer cells (see the rejections above) and noting that Abubakar et al teach that the method of Ki-67 staining would be expected to predictably function in invasive tumor cells (see for example, column 2 of page 10 of Abubakar et al). Therefore, the prior art references are deemed to make obvious before the effective filing date of the invention the instant claim(s) with a reasonable expectation of success.
Regarding claim 4, the combined prior art references teach and make obvious instant claim 1 wherein the cancer or tumor cells are breast cancer cells (see the rejections above). Dako further teaches and suggests that 10% positive biomarker staining is a relevant threshold for certain cancers (see for example, pages 2, 6, and 9-13 [“Near cut-off specimens were defined as specimens with CPS [combined positive score] score ≥ 1 and <20 for CPS ≥10”]). Therefore, the prior art references are deemed to make obvious before the effective filing date of the invention the instant claim(s) with a reasonable expectation of success.
Regarding claim 5, the combined prior art references teach the method of claim 1 and Abubaker et al teach that Ki-67 staining was nuclear staining (see for example, pages 3-4 and 9-10). With respect to the recitation that the staining is throughout the entire chromatin distribution, this recitation is not an active step, but merely reflects a result naturally flowing from practicing the recited active method steps using the recited products (such that one practicing the method of Abubakar et al would have observed the recited chromatin distribution staining, absent evidence to the contrary which would very likely indicate deficiencies in the claim with respect to the requirements of 35 USC 112(a)). Alternatively, where the recited complete nuclear staining is intended to reflect an active selection/inclusion step rather than a result, this is understood to require either any nuclear staining or complete nuclear staining(see the new claim interpretation section above) (as the claim is drafted with the connecter ‘or’). Either way, both of these optioned have been recited in claim 1 and are deemed to be made obvious by the combined prior art references for reasons iterated in the rejection of claim 1 above. Therefore, the prior art references are deemed to make obvious before the effective filing date of the invention the instant claim(s) with a reasonable expectation of success.
Regarding claim 6, the combined prior art references teach the method of claim 1 and Abubakar et al teach that the staining is accomplished used brown DAB (see for example, pages 4 and 11). Therefore, the prior art references are deemed to make obvious before the effective filing date of the invention the instant claim(s) with a reasonable expectation of success.
Regarding claim 7, the combined prior art references teach the method of claim 1 and Dako et al teach that tumor cells with only cytoplasmic staining were excluded from the numerator. Understanding that Abubakar et al teach that Ki-67 staining of interest is nuclear, the artisan would have found it obvious to exclude tumor/cancer cells with only cytoplasmic staining from the numerator (Ki-67 positively stained, viable tumor/cancer cells), meeting the limitation of instant claim 7(a) (see for example, table 2 at page 7 of Dako; see further for example, the above rejections over Abubakar et al and Dako). Therefore, the prior art references are deemed to make obvious before the effective filing date of the invention the instant claim(s) with a reasonable expectation of success.
Regarding claim 8, the combined prior art references teach the method of claim 1 and Abubakar et al teach that, in the majority of cores, more than 1000 cells were counted even though fewer than this number was counted in a small minority. Overall, cores with more than 500 cells were considered to be of satisfactory quality. This would have suggested to the artisan the desirability of using samples having a similar number of cells for Ki-67 staining and scoring (see for example, column 1 of page 4 of Abubakar et al; noting that this teaching is deemed to read on the limitation of having at least 100 cells as recited in instant claim 8 (a)). Therefore, the prior art references are deemed to make obvious before the effective filing date of the invention the instant claim(s) with a reasonable expectation of success.
Regarding claim 9, the combined prior art references teach and make obvious the
methods of claim 1 wherein the cancer/tumor is breast cancer (see the rejections of claims 1 and 3-8 above). Therefore, the prior art references are deemed to make obvious before the effective filing date of the invention the instant claim(s) with a reasonable expectation of success.
Regarding clam 10, the combined prior art references teach and make obvious the
methods of claim 1, wherein Abubakar et al teach the use of samples generally having 1,000 cells (with cores with more than 500 cells were considered to be of satisfactory quality) (see for example, column 1 of page 4 of Abubakar et al) and Dako teaches that 1% of cells staining positive for a biomarker of interest is of diagnostic relevance for 4 out of 5 cancers investigated (see for example, page 2 of Dako; noting that Dako examines PD-L1 expression in 5 cancers, not including breast cancer, but understanding that this would lead the artisan to investigate the relevance of 1% positive staining for other biomarkers of interest, such as Ki-67 in relation to other cancers, such as breast cancer where Abubakar et al teach that Ki-67 expression is relevant for breast cancer (see the rejections of claims 1 and 3-10 above). Abubakar et al teach that 12% of positively stained cells (using their automated counting means, correlating with 25% of cells by visual scoring) was of particular prognostic relevance in their population studied (breast cancer) (see for example, column 1 of page 10). Where the majority of the cores of Abubakar et al had more than 1,000 cells, and Abubakar et al further teach that 12% positive staining was relevant, indicating that 120 cells would have been positively stained and would have been adequate for evaluation. The artisan would have been guided towards these samples because Abubakar et al teach that samples having 12% staining as determinized by the method of Abubakar et al are of prognostic relevance. Furthermore, Dako teaches that a minimum of 100 viable tumor cells must be present in the PD-L1 stained slide for the specimen to be considered adequate for PD-L1 evaluation (see for example, page 6 at the first paragraph under the Interpretation of PD-L1 Staining section).
It would have been prima facie obvious before the effective filing date of the invention to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Abubakar et al and Dako. The artisan would have been motivated to make and use the invention as claimed because Abubakar et al teach the desirability of standardizing scoring of Ki-67 expression for diagnosis/treatment of breast cancer and teach means for said standardization. The artisan, understanding that there are multiple means for mathematically standardizing and reporting biomarker expression data would have found it obvious to use any means known in the art for said quantification. The artisan would have been guided to use the method taught by Dako because both Dako and Abubakar et al are concerned with quantitively reporting biomarker expression data from cancer samples. Dako teaches that a sample must have a minimum of 100 viable tumor cells to be adequate for biomarker evaluation. This is not the same as saying that those 100 minimum cells must be positively stained viable cells. However, Abubakar et al, teaching that cores generally having 1,000 cells are of prognostic value having 12% positively stained viable cells would guide the artisan to look at tissue samples having at about 100 positively stained (for Ki-67 as taught by Abubakar et al), viable cancer/tumor cells for evaluation of Ki-67 expression for prognostic purposes (as is the aim of both Abubakar et al (see for example, pages 1-2 and 10) and Dako (see for example, pages 1-2)). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 13 and 17, as discussed above, the combined prior art references teach and make obvious instant claim 1. Abubakar et al teach that Ki-67 staining is accomplished using the MIB-1 antibody clone (see the rejections of claims 1, 3-10, and 12 above), which makes obvious part (b) of claim 13 and claim 17. Therefore, the prior art references are deemed to make obvious before the effective filing date of the invention the instant claim(s) with a reasonable expectation of success.
Regarding claim 14, as discussed above, Abubakar et al and Dako teach and make obvious instant claim 1.
Dako further teaches a kit that contains the mouse monoclonal anti PD-L1 clone 22C3 antibody and reagents required to complete an immunohistochemical staining procedure for formalin fixed and paraffin-embedded (FFPE) specimens using the Dako Autostainer Link 48 with DakoLink software and the EnVision FLEX visualization system. Each kit includes 19.5 mL of PD-L1 primary antibody (approximately 3μg/mL protein concentration) and reagents necessary to perform test. Wash buffer and hematoxylin are required for the assay but not included in the kit (see for example, pages 3-4). The key difference between the teachings of Dako and the teachings of Abubakar et al pertain to the biomarker of interest, PD-L1 and Ki-67, respectively. Otherwise, the two sources are remarkably similar, employing Dako antibodies, reagents, and autostainer (see for example page 3, column 2 of Abubakar et al). The only additional limitation added is that the kit comprises scoring guidelines according to the method of instant claims 1-13 (said scoring guidelines being indefinite, as discussed in the rejections under 35 USC 112(b) above). This amounts to a recitation of written instructions which does not alter the components or function of claimed methods. The teachings of the prior art, making obvious the methods of claims 1-13 make obvious the recited instructions. Therefore, the kit of claim 14 is deemed obvious in light of the cited prior art. It is further noted the terminology “kit” is not found to further limit the scope of the claims beyond requiring the inclusion of the reagent for measuring an expression level of Ki-67, as it does not clearly invoke any additional ingredients or provide the antecedent basis for terms appearing in the body of the claim (such as specific packaging or container elements, for example) (see MPEP § 2111.02). Consequently, when the claims are given their broadest reasonable interpretation, because Abubakar et al and Dako teach the same structural components that applicant refers to as a kit, the teachings of Abubakar et al and Dako address the claimed elements/limitations.
Therefore, the prior art references are deemed to make obvious before the effective filing date of the invention the instant claim(s) with a reasonable expectation of success.
New-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.
Claim 1, 3, 5-6, 8-9, 12-13, 15, and 17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-6, 8, 11, 15-16, 18, 20-23, 25, 27, and 31-32 of copending Application No. 18/208,178 (reference A) in view of Abubakar et al (Breast Cancer Res. 2016 Oct 18;18(1):104. doi: 10.1186/s13058-016-0765-6), Skjulsvik et al (Int J Clin Exp Pathol. 2014 Dec 1;7(12):8905-10), and Rizzardi et al (Diagn Pathol 7, 42 (2012). https://doi.org/10.1186/1746-1596-7-42).. The claims are both directed to methods of immunohistochemical analysis of biomarker expression in cancer/tumor cells and cell quantification therefrom.
This is a provisional nonstatutory double patenting rejection.
Regarding claims 1, 12, and 15, reference A claims an immunohistochemistry (IHC) method for determining and scoring the extent of cellular membrane expression of carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) in a tissue sample, comprising: (a) staining a tissue sample with an antibody which specifically binds to CEACAM5; (b) determining a total number of viable tumor or cancer cells having CEACAM5 cellular membrane staining, and determining a total number of staining and non-staining viable tumor or cancer cells in at least a portion of the tissue sample, wherein a tumor or cancer cell is counted as positively stained with anti-CEACAM5 antibody if there is CEACAM5 cellular membrane staining at any intensity above a defined threshold; and (c) determining a Tumor Intensity Proportion Score, wherein the Tumor Intensity Proportion Score is the number of CEACAM5 staining viable tumor or cancer cells found in the tissue sample divided by the total number of staining and non-staining viable tumor or cancer cells, multiplied by 100.
Reference A does not claim the use of an antibody to determine expression of Ki-67 showing complete nuclear staining.
However, Abubakar et al teach the International Ki-67 in Breast Cancer Working Group published recommendations aimed at the standardization of the analytical processes for Ki-67 evaluation. Aiming for said standardization, Abubakar et al used tissue micro arrays containing tumour tissue cores from breast cancer patients. Staining was accomplished using a Dako autostainer and a standard protocol with Dako MIB-1 diluted 1/50 and visualized using the Dako REAL kit (K5001) [Note that the MIB-1 antibody is also used as an anti-Ki-67 antibody by Applicant (see for example, lines 3-6 of page 3 of the instant specification) (see also, for example, the abstract’s method section at page 1, column 1 of page 2, and column 2 (at the KI67 immunostaining section) of page 3 of Abubakar et al). Note that this teaching is deemed to teach contacting the sample with the antibody binding Ki-67. Regarding invasive tumors, Abubakar et al teach and suggest predictability for using Ki-67 staining in invasive tumor TMAs by teaching an excellent correlation was observed between Ki-67 staining in TMAs and whole sections (teaching both the desirability of examining Ki-67 and the use of the method of Abubakar et al for such examination with a reasonable expectation of success) (see for example, column 2 of page 10). Abubakar et al teach that there are various means known in the art for scoring Ki-67 (by hand scoring by a pathologist and automated scoring-both of which were used by Abubakar et al (see for example, column 1 of page 3). Abubakar et al teach scoring to achieve a % Ki-67 (see for example, Figure 1 and its caption at page 3).
Reference A and Abubakar et al do not explicitly mention ‘complete nuclear staining’.
However, Skjulsvik et al teach, as part of a discussion of Ki-67 immunostaining, that because expression of the Ki-67 antigen changes during the cell cycle, the intensity of nuclear staining will vary; principally, all types of staining should be regarded as positive (see for example, column 2 of page 8908 (noting that robust nature of Ki-67 staining with MIB-1 is discussed in column 1 of page 8908 and the observed homogenous distribution of Ki-67 throughout tumor tissue (see column 2 of page 8907))).
Reference A, Abubakar et al, and Skjulsvik et al do not teach that IHC expression scoring is conducted on a scale of 1+ or higher.
However, Rizzardi et al teach that, traditionally, pathologists have visually scored IHC data. For example, in the calculation of an HSCORE, a summation of the percentage of area stained at each intensity level multiplied by the weighted intensity (e.g., 1, 2, or 3; where 0 is no staining, 1 is weak staining, 2 is moderate staining and 3 is strong staining) of staining is generated. These analyses are frequently performed on specimens arrayed on stained TMA sections allowing representation of a sufficiently large number of specimens for statistically rigorous testing. Tissue specimens are adequately represented by tissue cores on very few slides minimizing IHC cost and tissue usage, and facilitating intra-observer, inter-observer and inter-laboratory studies (see for example, column 1 of page 2).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of reference A and Abubakar et al. The artisan would have been motivated to make and use the invention as claimed because Abubakar et al teach desirability of standardizing scoring of Ki-67 expression for diagnosis/treatment of breast cancer and teach means for said standardization. The artisan, understanding that there are multiple means for mathematically standardizing and reporting biomarker expression data would have found it obvious to use any means known in the art for said quantification. The artisan would have been guided to use the method claimed by reference A because both reference A and Abubakar et al are concerned with quantitively reporting biomarker expression data from cancer samples, such that interchanging the biomarker of reference A (CEACAM5) for the biomarker of Abubakar et al (Ki-67; understood to be nuclear staining using the MIB-1 antibody) for prognostic purposes in breast cancer would have been obvious to the artisan. Regarding the recitation of complete nuclear staining, see the claim interpretation section above noting that the only described definition would be staining that is homogenous throughout the chromatin and has an intensity of 1 or greater. Rizzardi et al, concerned with scoring of intensity for biomarkers in histological samples teaches that scoring on a scale of 1+-3+ is traditionally used in the art, where 0 is traditionally used to indicate a negative result and 1+ indicates weak staining/expression of the biomarker of interest and Skjulsvik et al teach that, with respect to Ki-67 nuclear staining, any staining should be regarded as positive, but notes with particularity that homogenous distribution was observed in tumor tissue samples (see for example, pages 8907-8908 of Skjulsvik et al as well as the rejection of this claim above). The artisan would have found it obvious to use art known means of scoring intensity, such as the method taught by Abubakar et al and Dako through the scoring means of Rizzardi et al and the indications of positive/negative expression staining for Ki-67 as taught by Skjulsvik et al for prognostic purposes (see for example, the abstract of Abubakar et al at page 1). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 3, the combined references teach and make obvious instant claim 1 wherein the cancer or tumor cells are breast cancer cells (see the rejections above).
Regarding claim 5, Abubaker et al teach that Ki-67 staining was nuclear staining (see for example, pages 3-4 and 9-10). With respect to the recitation that the staining is throughout the entire chromatin distribution, this recitation is not an active step, but merely reflects a result naturally flowing from practicing the active method steps using the recited products (such that one practicing the method of Abubakar et al would have observed the recited chromatin distribution staining, absent evidence to the contrary which would very likely indicate deficiencies in the claim with respect to the requirements of 35 USC 112(a)). Alternatively, where the recited complete nuclear staining is intended to reflect an active selection/inclusion step rather than a result, this is understood to require either any nuclear staining or complete nuclear staining(see the new claim interpretation section above) (as the claim is drafted with the connecter ‘or’). Either way, both of these optioned have been recited in claim 1 and are deemed to be made obvious by the combined prior art references for reasons iterated in the rejection of claim 1 above.
Regarding claim 6, Abubakar et al teach that the staining is accomplished used brown DAB (see for example, pages 4 and 11).
Regarding claim 8, Abubakar et al teach that, in the majority of cores, more than 1000 cells were counted even though fewer than this number was counted in a small minority. Overall, cores with more than 500 cells were considered to be of satisfactory quality. This would have suggested to the artisan desirability of using samples having a similar number of cells for Ki-67 staining and scoring (see for example, column 1 of page 4 of Abubakar et al; noting that this teaching is deemed to read on the limitation of having at least 100 cells as recited in instant claim 8 (a)).
Regarding claim 9, the combined references teach and make obvious the
methods of claims 1, 3-6, and 8 wherein the cancer/tumor is breast cancer (see the rejections of claims 1, 3-6, and 8 above).
Regarding claims 13 and 17, Abubakar et al teach that Ki-67 staining is accomplished using the MIB-1 antibody clone (see the rejections of claims 1 ,3-6, and 8-9 above), which makes obvious part (b) of claim 13 and claim 17.
Claim 4, 7, 10, and 14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-6, 8, 11, 15-16, 18, 20-23, 25, 27, and 31-32 of copending Application No. 18/208,178 (reference A) in view of Abubakar et al, Skjulsvik et al, and Rizzardi et al, as applied to claims 1, 3, 5-6, 8-9, 12-13, 15, and 17 above, in further view of Dako (FDA SSED for PD-L1 HC 22C3 pharmDx, obtained from: https://www.accessdata.fda.gov/cdrh_docs/pdf15/P150013S016B.pdf, (FDA approval on 07/30/2019) (Proof of availability further supported by the Google screen capture)). The claims are both directed to methods of immunohistochemical analysis of biomarker expression in cancer/tumor cells and cell quantification therefrom.
This is a provisional nonstatutory double patenting rejection.
Regarding claim 4, the combined references teach and makes obvious instant claim 1 wherein the cancer or tumor cells are breast cancer cells (see the rejections above). Dako further teaches and suggests that 10% positive biomarker staining is a relevant threshold for certain cancers (see for example, pages 2, 6, and 9-13[“Near cut-off specimens was defined as specimens with CPS score ≥ 1 and <20 for CPS ≥10”]).
Regarding claim 7, Dako et al teach that tumor cells with only cytoplasmic staining were excluded from the numerator. Understanding that Abubakar et al teach that Ki-67 staining of interest is nuclear, the artisan would have found it obvious to exclude tumor/cancer cells with only cytoplasmic staining from the numerator (Ki-67 positively stained, viable tumor/cancer cells), meeting the limitation of instant claim 7(a) (see for example, table 2 at page 7 of Dako; see further for example, the above rejections over Abubakar et al and Dako).
Regarding clam 10, the combined references teach and make obvious the
methods of claims 1 and 3-9, wherein Abubakar et al teach the use of samples generally having 1,000 cells (with cores with more than 500 cells were considered to be of satisfactory quality) (see for example, column 1 of page 4 of Abubakar et al, where Dako teaches that 1% of cells staining positive for a biomarker of interest is of diagnostic relevance for 4 out of 5 cancers investigated (noting that Dako examines PD-L1 expression in 5 cancers, not including breast cancer, but understanding that this would lead the artisan to investigate the relevance of 1% positive staining for other biomarkers of interest, such as Ki-67 in relation to other cancers, such as breast cancer where Abubakar et al teach that Ki-67 expression is relevant for breast cancer (see for example, page 2 of Dako)). Abubakar et al teach that 12% is positively stained cells (using their automated counting means, correlating with 25% of cells by visual scoring) was of particular prognostic relevance in their population studied (breast cancer) (see for example, column 1 of page 10). Where the majority of the cores of Abubakar et al had more than 1,000 cells, and Abubakar et al further teach that 12% positive staining was relevant, indicating that 120 cells would have been positively stained and would have been adequate for evaluation. The artisan would have been guided towards these samples because Abubakar et al teach that samples having 12% staining by the method of Abubakar et al are of prognostic relevance. Furthermore, Dako teaches that a minimum of 100 viable tumor cells must be present in the PD-L1 stained slide for the specimen to be considered adequate for PD-L1 evaluation (see for example, page 6 at the first paragraph under the Interpretation of PD-L1 Staining section).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of reference A, Abubakar et al, and Dako. The artisan would have been motivated to make and use the invention as claimed because Abubakar et al teach desirability of standardizing scoring of Ki-67 expression for diagnosis/treatment of breast cancer and teach means for said standardization. The artisan, understanding that there are multiple means for mathematically standardizing and reporting biomarker expression data would have found it obvious to use any means known in the art for said quantification. The artisan would have been guided to use the method taught by Dako because reference A, Dako, and Abubakar et al are concerned with quantitively reporting biomarker expression data from cancer samples. Dako teaches that a sample must have a minimum of 100 viable tumor cells to be adequate for biomarker evaluation. This is not the same as saying that those 100 minimum cells must be positively stained viable cells. However, Abubakar et al, teaching that cores generally having 1,000 cells are of prognostic value having 12% positively stained viable cells would guide the artisan to look at tissue samples having at about 100 positively stained (for Ki-67 as taught by Abubakar et al), viable cancer/tumor cells for evaluation of Ki-67 expression for prognostic purposes (as is the aim of both Abubakar et al (see for example, pages 1-2 and 10) and Dako (see for example, pages 1-2)). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 14, as discussed above, the combined references teach and make obvious instant claims 1, 3-10, and 13.
Dako further teaches a kit that contains the mouse monoclonal anti PD-L1 clone 22C3 antibody and reagents required to complete an immunohistochemical staining procedure for formalin fixed and paraffin-embedded (FFPE) specimens using the Dako Autostainer Link 48 with DakoLink software and the EnVision FLEX visualization system. Each kit includes 19.5 mL of PD-L1 primary antibody (approximately 3μg/mL protein concentration) and reagents necessary to perform test. Wash buffer and hematoxylin are required for the assay but not included in the kit (see for example, pages 3-4). The key difference between the teachings of reference A, Dako and the teachings of Abubakar et al pertain to the biomarker of interest, CPD-L1 and Ki-67, respectively. Otherwise, the prior art and copending sources are remarkably similar, employing Dako antibodies, reagents, and autostainer (see for example page 3, column 2 of Abubakar et al). The only additional limitation added is that the kit comprises scoring guidelines according to the method of instant claims 1-13 (said scoring guidelines being indefinite, as discussed in the rejections under 35 USC 112(b) above). This amounts to a recitation of written instructions which does not alter the components or function of claimed methods. The teachings of the prior art, making obvious the methods of claims 1-13 make obvious the recited instructions. Therefore, the kit of claim 14 is deemed obvious in light of the cited prior art. It is further noted the terminology “kit” is not found to further limit the scope of the claims beyond requiring the inclusion of the reagent for measuring an expression level of Ki-67, as it does not clearly invoke any additional ingredients or provide the antecedent basis for terms appearing in the body of the claim (such as specific packaging or container elements, for example) (see MPEP § 2111.02). Consequently, when the claims are given their broadest reasonable interpretation, because reference A, Abubakar et al, and Dako teach the same structural components that applicant refers to as a kit, the teachings of the combined references address and make obvious the claimed elements/limitations.
Applicant’s Arguments and Responses:
A. Applicant argues for withdrawal of the objection to the drawings citing filing of a Petition for Color Drawings on 03/13/2026 (see page 9 of the 03/13/2026 remarks).
Response: Filing of a petition is insufficient to overcome the objection. The petition must be accepted in order for the objection to be overcome. No acceptance of the petition is present in the record. Therefore, the objection to the drawings is maintained.
B. Applicant argues for withdrawal of the rejections under 35 USC §112(a) for lack of written description by distinguishing that Amgen v. Sanofi is different than the present fact pattern because the instant claims are directed to a method where the antibodies are auxiliary to the invention (see pages 9-10 of the 03/13/2026 remarks).
Response: While the facts of Amgen v Sanofi do not directly align to the present case, the opinion is still instructive for claims including antibodies. Further Amgen v Sanofi was not cited in isolation, but was included in an analysis which also cited University of Rochester v. G.D. Searle and Co. (69 USPQ 2nd 1886, CAFC 2004) and Ariad Pharmaceuticals., Inc. v. Eli Lilly & Co., 94 USPQ2d 1161, 1173 (Fed. Cir. 2010) (en banc), which support the application of the written description requirement for a genus of antibodies included in a larger method. The rejection is maintained at this time.
C. Applicant argues for withdrawal of the rejections of claims 8-9 under 35 USC §112(a) for lack of enablement because the Ki-67 antibodies are not themselves being used therapeutically and the instant specification, most easily referred to and referenced by looking to the Pre-grant Publication US 2024/0295559 A1 sufficiently enables the method claims at paragraphs 0061 and 0063-0064 of US 2024/0295559 A1 (see pages 10-11 of the 03/13/2026 remarks).
Response: The rejection clearly states that the use of the Ki-67 score to determine/implement administration of a cancer therapeutic/treatment. The rejection pertains to using the Ki-67 score to guide/implement administration of a cancer therapeutic/treatment and respectfully does not confuse the method as being directed to use of the Ki-67 antibodies as therapeutic. As noted in the rejection, the prior art demonstrates that cancer is a genus of heterogenous disease with no single cure. The prior art does not enable the method. Looking to the paragraphs that Applicant points to, paragraph 0061 recites multiple references. These references do not appear to teach the use of a Ki-67 score (%) to guide/implement treatment of cancer, but merely show a correlation between certain cancers or outcomes and Ki-67 (see for example the cited references Li et al (Mol Med Rep. 2015 March, 11(3):1566-72) and Zhou et al (2017 Medicine (Baltimore) August; 96 (34):e7911) at paragraph 0061 of US 2024/0295559 A1). Paragraph 0063 of US 2024/0295559 A1 notes that “[d]espite extensive effort spent on evaluating Ki67 as a prognostic and/or predictive marker in the past three decades, this biomarker is still not completely integrated into clinical decision making mainly because of the lack of standardization and reproducibility in staining techniques and Ki67 scoring method”, which acknowledges the level of unpredictability in the art and underscores the concerns noted in the enablement rejection. It is further noted that even if these reference were, hypothetically, taken to be enabling, the entire claimed genus of cancer would still not be fully enabled as recited in the claims. Therefore, the rejection is maintained at this time.
D. Applicant argues for withdrawal of the rejections under 35 USC 112(b) alleging that the claim amendments dated 03/13/2026 overcome the rejections by correcting the ambiguities noted in said rejections (see page 11 of the remarks dated 03/13/2026).
Response: The maintained rejections have not been amended to correct the problems noted in the rejections under 35 USC §112(b).There being no further argument to consider, the rejections are maintained.
Conclusion
No claim is allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Dowsett et al (JNCI: Journal of the National Cancer Institute, Volume 103, Issue 22, 16 November 2011, Pages 1656–1664, https://doi.org/10.1093/jnci/djr393) is deemed relevant.
Agilent (US 20170285029 A1; cited as citation 1 under US patent literature on the 03/09/2023 IDS) teaches methods for determining the eligibility of a subject having a malignancy for treatment with an anti-PD therapeutic agent, said methods include determining, by immunohistochemistry, the number of PD-L1 positive malignant cells in a tumor tissue section (see for example, the abstract). The scores are recorded as actual percent PD-L1 positive malignant cells per total malignant cells (% PD-L1 positively stained malignant cells (MC)/ (total [stained and non-stained] malignant cells (TMC)) (see for example, paragraphs 0080-0081). Note that the percentage score of Agilent is a ratio, not a true percentage.
US20180182099 A1 (cited as citation 3 under US patent literature on the 03/09/2023 IDS) is deemed relevant.
JP201052966 A (cited as citation 1 under foreign patent documents on the 06/24/2025 IDS) is deemed relevant.
JP2013200287 A (cited as citation 3 under foreign patent documents on the 06/24/2025 IDS) is deemed relevant.
WO2019168085 A1 (cited as citation 5 under foreign patent documents on the 06/24/2025 IDS) is deemed relevant.
The references cited on the 11/20/2024 IDS are deemed relevant.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
Prosecution Insights