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 .
Application and Claims Status
Applicant’s preliminary amendments filed on February 4, 2026 are acknowledged and entered.
Claims 1-3, 6-14, 16-21, 23, and 25 were pending. In the amendment as filed on February 4, 2026, applicants have amended claims 1, 9, 16, and 17; cancelled no claims; and added no new claims. Therefore, claims 1-3, 6-14, 16-21, 23, and 25 are currently pending.
Election/Restrictions
This action is in response to an election from a Restriction Requirement filed on December 10, 2025. Applicant’s election with traverse of Group I, directed to compounds of formula (I), which reads on claims 1-3, 6-14, 17-18, and 20, in the reply filed on February 2, 2026 is acknowledged. Applicant argues that Group I and II should belong to the same invention. Due to the amendment of claim 16 from an independent claim to explicitly dependent upon claim 1, Group I now includes Group I and II from the Restriction Requirement and reads on claims 1-3, 6-14, 16-18, and 20. Examiner finds this persuasive.
Applicant has not provided an argument for the traversal of Groups III and IV by distinctly pointing out the supposed errors in the restriction requirement so Group I is elected without traverse with respect to Groups III and IV. Therefore, the requirement is still deemed proper and is therefore made FINAL.
Applicant further elected the species 26-1, shown below. Examination will be limited to claims directed to the elected species, which are presently claims 1-3, 6-14, 16, 19-21, 23 and 25, to the extent that they are readable on the elected embodiment.
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The elected species has been found to be free of prior art, thus examination was extended to all compounds of formula (I).
Claims 19, 21, 23, and 25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Therefore, claims 1-3, 6-14, 16-18, and 20 are presently under examination. Applicant timely traversed the restriction (election) requirement in the reply filed on February 2, 2026.
Priority
The instant application is a U.S. national stage application of International Patent Application No. PCT/CN2022/083597, filed on March 29, 2022, which claims the benefit and priority of Chinese patent application No. 202110332995.1, filed on March 29, 2021, No. 202110666964.X, filed on June 16, 2021, No. 202110870938.9, filed on July 30, 2021, and No. 202111097026.9, filed on September 18, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) filed on September 28, 2023 is in compliance with the provisions of 37 CFR 1.97. All references have been considered except where marked with a strikethrough. A signed copy of Form 1449 is included with this Office Action.
Examiner Interpretation
Claim 6 recites linker groups (L) that have attachment points on each of their left- and right-hand sides. Since the specification or claims do not mention through which point of attachment each linker is attached to the two portions of the molecule, the Examiner infers that each linker can be flipped. So, for instance, with respect to the second linker shown in instant claim 6, the possible linker attachment options are both shown below:
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Specification – Disclosure
The labeling of compounds in the Specification (Table A, page 19-52) is inconsistent. For instance, on page 19-20, the second example of Table A is labeled 2-1, while its separated diastereomers are not given any labeling.
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any of the errors of which applicant may become aware of in the specification.
Specification - Drawings
Acknowledgement is made of the drawings received September 28, 2023.
The drawings are objected to because:
The numbering on the page is currently located at the bottom of the drawings, and the drawing sheet numbering must be larger than the numbers used as reference characters. As recited in 37 CFR 1.84:
(t) Numbering of sheets of drawings. The sheets of drawings should be numbered in consecutive Arabic numerals, starting with 1, within the sight as defined in paragraph (g) of this section. These numbers, if present, must be placed in the middle of the top of the sheet, but not in the margin. The numbers can be placed on the right-hand side if the drawing extends too close to the middle of the top edge of the usable surface. The drawing sheet numbering must be clear and larger than the numbers used as reference characters to avoid confusion. The number of each sheet should be shown by two Arabic numerals placed on either side of an oblique line, with the first being the sheet number and the second being the total number of sheets of drawings, with no other marking.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections – Minor Informalities
Claims 14 is objected to because it uses the open ended “and/or” within a closed grouping. The claim from which it depends, claim 1, uses a closed Markush listing of alternatives, while claim 14 uses the open-ended “and/or”. The use of closed group language in combination with open group language is improper. Examiner suggests amending “and/or” to “and”. Appropriate correction is required.
Claim 16 is objected to because of the following informalities:
Some of the claimed compounds contain identifying numbers that were pulled from the specification. These numbers should not be in the claim. For instance, the very first compound of claim 16 is labeled 1, the second one is labeled 2-1. These labels should be removed.
It contains multiple duplicate species, enumerated below:
On page 14: col 1, row 6; col 2, row 6
On page 16: col 1, row 6; col 2, row 5
On page 19: col 1, row 6, col 2, row 5
On page 22: col 1, row 4; col 2, row 3
On page 24: col 1, row 4; col 2, row 3; col 2, row 5
On page 25: col 1, row 2; col 2, row 1
On page 25: col 1, row 5; col 2, row 5
On page 26: col 1, row 3; col 2, row 3
On page 27: col 1, row 1; col 2, row 1
Applicant’s cooperation is requested in correcting any of the duplicate structures within the claim.
The preamble should state “The compound of claim 1…” Appropriate correction is required.
Claims 20 is objected to because of the following informality: the claim is not consistent with proper Markush practice. The claims should be listed in the singular, alternative format. As an example, the examiner suggests that claim 20 be rewritten to read, “…and one or more of a pharmaceutically acceptable carrier, diluent, or excipient” so as to be consistent with proper Markush practice. No new matter permitted. Appropriate action is required.
Claim Rejections – Improper Markush Grouping
Claims 1-3, 6-14, 17, and 20 are rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature.
A Markush claim contains an “improper Markush grouping” if: (1) the species of the Markush group do not share a “single structural similarity,” or (2) the species do not share a common use. Members of a Markush group share a "single structural similarity” when they belong to the same recognized physical or chemical class or to the same recognized physical or chemical class or to the same art-recognized class. Members of a Markush group share a common use when they are disclosed in the Specification or known in the art to be functionally equivalent (see Federal Register, Vol. 76, No. 27, Wednesday, February 9, 2011, p. 7166, left and middle columns, bridging paragraph). If (1) or (2) apply to a Markush grouping, a rejection under the judicially approved “improper Markush grouping” doctrine is proper.
Regarding claim 1, the members of the improper Markush grouping do not share a substantial feature and/or a common use that flows from the substantial structural feature for the following reasons:
The variable is defined as seen below:
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As the artisan could observe, the only common feature among the molecules above is that the left-hand portion is a [6,6]-ring fused system and the right-hand portion contains a [6,5]-ring fused system attached to a cyclic imide. There are no required structural features in common such that each member of formula (I) would have at least one structural feature, which feature is essential to the activity/function of the claimed compound. One would not expect all of these compounds to be alternatively usable. The ring systems depicted above represent a sampling of the numerous and various core structures of the compound of formula (I) as recited in claim 1. However, these core structures exhibit no discernible structural similarity. One 6-membered ring can have four G variables with all combinations of carbon and nitrogen, a variety of linker groups, many combinations of carbon and nitrogen atoms for the Z variables of the [6,5]-ring fused system, and variable linker attachment points to this ‘thalidomide-like’ structure. Furthermore, the Markush group of formula (I) contains a plethora of nested variables for R3a, R3b, R2, G1-G4, and Z1-Z4. Clearly no ‘‘single structural similarity’’ can be seen. In the absence of evidence to the contrary, all compounds within the metes and bounds of the extraordinarily large Markush grouping of the instant claims cannot be individually envisioned and each expected to be functionally equivalent.
Since the dependent claims 2-3, 6-14, 20 do not resolve the improper Markush grouping, they are similarly rejected.
Regarding claim 17, the members of the improper Markush grouping do not share a substantial feature and/or a common use that flows from the substantial structural feature for the following reasons:
The variable is defined as seen below:
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As the artisan could observe, the only common feature among the molecules above is that the left-hand portion is a [6,6]-ring fused system. There are no required structural features in common such that each member of formula (I) would have at least one structural feature, which feature is essential to the activity/function of the claimed compound. One would not expect all of these compounds to be alternatively usable. The ring systems depicted above represent a sampling of the numerous and various core structures of the compound of formula (IIIa) as recited in claim 17. However, these core structures exhibit no discernible structural similarity. One 6-membered ring can have four G variables with all combinations of carbon and nitrogen, a variety of j lengths, and X can be oxygen or carbon. Furthermore, the Markush group of formula (IIIa) contains a plethora of nested variables for R3a, R3b, R2, and G1-G4. Clearly no ‘‘single structural similarity’’ can be seen. In the absence of evidence to the contrary, all compounds within the metes and bounds of the extraordinarily large Markush grouping of the instant claims cannot be individually envisioned and each expected to be functionally equivalent.
In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. § 134 and 37 CFR41.31 (a) (1) (emphasis provided).
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 2-3, 6-7, 9-14 and 20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites that “L is a linker unit”. The inventor or joint inventor should note that claim 1 is a reach-through claim. The claim attempts to obtain protection for subject matter that is prophetic and/or has yet to be invented, including any linker unit that has not yet been invented. Similarly, the metes and bounds of a “linker group” are not defined by the claim, the specification does not provide an adequate standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the metes and bounds of the invention. The phrase “L is a linker unit” does not confer any known structure. On page 2 of the specification, Applicant only discloses “the two ligands are linked by a linker arm” and on pages 5-6, teaches numerous, nonlimiting embodiments of linker groups. Consequently, the compound of formula (I) comprising a “linker group” have been rendered indefinite by the use of the reach-through protocol.
Claims 6, 8, and 16 do confer structure onto the linker group. However, claims 2-3, 7, 9-14, and 20 are rejected as being dependent upon claim 1 and failing to give structure to L.
Claim 1 recites the limitation, “one of Z1, Z2, Z3, and Z4 is a carbon atom, and the remaining three are identical or different and are each independently a nitrogen atom or CR8”, which the Examiner regards as vague, specifically in the use of “or different”. Does this limitation mean that if, as an example, Z1 is a carbon atom, then then remaining three are either all identical (to Z1 =C) so all carbon (Z2, Z3, Z4 = C) or all different (to Z1 = C) so all nitrogen (Z2, Z3, Z4 = N); or does this limitation mean, when it recites “or different”, that Z2, Z3, Z4 can simply be any combination of carbon and nitrogen that Applicant chooses (i.e. Z2, Z3 = C, Z4 = N; or Z2, Z3 = N, Z4 = C; or, Z3, Z4 = N, Z2 = C…). Clarification and correction are required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Scope of Enablement - Compounds
Claims 1-3, 6-14, and 20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the following:
A compound having a structure of formula (I) (as recited in Claim 1), or a pharmaceutically acceptable salt thereof
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or a pharmaceutical composition comprising a compound having a structure represented by formula I (as recited in claim 20) wherein:
L is always bonded to Z2;
X is O or CH2, as recited in claim 1;
G1-G4 are CR7 only;
R7 is H, halogen, C1-3 alkyl only;
R4a and R4b are H only;
R1 is H, C1-3 alkyl only;
R2, R8, R9, and R10 are H; m is 0;
R5a and R5b are H, or together form oxo;
Z1 is CR8 or N; Z2, Z3, and Z4 are CR8 only;
L is as it appears in formula (III) of claim 8, where j = 0, shown below
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;
R3a and R3b are as recited in claims 9 and 10
does not reasonably provide enablement for elements that are outside the scope of the enabling elements listed above. 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 the invention commensurate in scope with these claims.
To be enabling, the specification of the patent application must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996). As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors:
1- the quantity of experimentation necessary,
2- the amount of direction or guidance provided,
3- the presence or absence of working examples,
4- the nature of the invention,
5- the state of the prior art,
6- the relative skill of those in the art,
7- the predictability of the art, and
8- the breadth of the claims
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention:
The nature of the invention relates to compounds of formula (I) in claim 1. Such compounds are useful for patients with estrogen receptor-positive breast cancer. This invention is also directed to compositions comprising said compounds.
Predictability of the art:
The hypothetical compounds in claim 1 would be unpredictable in terms of one skilled in the art being able to synthesize every possible compound claimed in instant claim 1. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
In terms of the law, MPEP 2107.03 states “evidence of pharmacological or other biological activity of a compound will be relevant to an asserted therapeutic use if there is a reasonable correlation between the activity in question and the asserted utility. Cross v. Iizuka, 753 F.2d 1040, 224 USPQ 739 (Fed. Cir. 1985); In re Jolles, 628 F.2d 1322, 206 USPQ 885 (CCPA 1980); Nelson v. Bowler, 626 F.2d 853, 206 USPQ 881 (CCPA 1980).” If correlation is lacking, it cannot be relied upon, Ex parte Powers, 220 USPQ 924; Rey-Bellet and Spiegelberg v. Engelhardt v. Schindler, 181 USPQ 453; Knapp v. Anderson, 177 USPQ 688. Indeed, the correlation must have been established “at the time the tests were performed”, Hoffman v. Klaus, 9 USPQ2d 1657.
Level of skill in the art:
An ordinary artisan in the area of drug development would have experience in synthesizing and screening chemical compounds for particular activities, such as a medical doctor or chemist. Screening of new drug candidates, while complex, is routine in the art. The process of finding new drugs that have in vitro activity against a particular biological target, (i.e., receptor, enzyme, etc.) is well known. Additionally, while high throughput screening assays can often be employed, developing a therapeutic method, as claimed, is generally not well-known or routine, given the complexity of certain biological systems.
The breadth of the claims:
The scope of the claims involves compounds of formula (I), shown below.
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Claim 1 is very broad in the number of variables and the options of substituents for each variable. There is an extremely large amount of hypothetical compounds included in claim 1.
The amount of direction provided, the presence or absence of working examples, and the quantity of experimentation necessary:
The specification provides the synthesis of approximately 43 unique compounds (more including all possible enantiomers) as well as the corresponding biological data for these 43 compounds. Synthesis methods are not taught in the specification to provide for the aforementioned variables to include all of the possible substituents listed in the claims. For example, there are no working examples of a compound of formula I wherein there is an R4a or R4b group other than hydrogen along the [6,6]-ring fused core, or where G1, G2, G3, and G4 are anything other than carbon. Further, since the structure of L is not defined by claim 1, there are an infinite number of compounds contained in formula (I). It would be expected that varying the heteroatoms in the rings (e.g., G1-G4, Z1-Z4) and Linker group units would change the reactivity of the compounds, and therefore may require alternate synthesis methods. It would require one skilled in the art, such as a chemist, to perform thousands of reactions to determine which compounds of formula (I) can be prepared and would likely require synthesis methods other than those provided in the specification. This is undue experimentation given the limited guidance and direction provided by Applicants.
Accordingly, the instant claims do not comply with the enablement requirement of 35 U.S.C. 112(a), since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Claims 2-3, 6-14, and 20, which are dependent on claim 1, are also rejected for further requiring and/or reciting elements that are outside the scope of the enabling elements listed above.
Claim 17 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the following:
A compound having a structure of formula (IIIa) (as recited in Claim 17), or a salt thereof,
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wherein:
X is O or CH2, as written in claim 1;
G1-G4 are CR7 only;
R7 is H, halogen, C1-3 alkyl only;
R4a and R4b are H only;
R1 is H, C1-3 alkyl only;
R2, R9, and R10 are H; m, j are 0;
R3a and R3b are as recited in claims 9 and 10
does not reasonably provide enablement for elements that are outside the scope of the enabling elements listed above. 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 the invention commensurate in scope with these claims.
The nature of the invention:
The nature of the invention relates to compounds of formula (IIIa) in claim 17. Such compounds are useful as intermediates towards the claimed compounds of claim 1.
Predictability of the art:
The hypothetical compounds in claim 17 would be unpredictable in terms of one skilled in the art being able to synthesize every possible compound claimed in instant claim 17. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
In terms of the law, MPEP 2107.03 states “evidence of pharmacological or other biological activity of a compound will be relevant to an asserted therapeutic use if there is a reasonable correlation between the activity in question and the asserted utility. Cross v. Iizuka, 753 F.2d 1040, 224 USPQ 739 (Fed. Cir. 1985); In re Jolles, 628 F.2d 1322, 206 USPQ 885 (CCPA 1980); Nelson v. Bowler, 626 F.2d 853, 206 USPQ 881 (CCPA 1980).” If correlation is lacking, it cannot be relied upon, Ex parte Powers, 220 USPQ 924; Rey-Bellet and Spiegelberg v. Engelhardt v. Schindler, 181 USPQ 453; Knapp v. Anderson, 177 USPQ 688. Indeed, the correlation must have been established “at the time the tests were performed”, Hoffman v. Klaus, 9 USPQ2d 1657.
Level of skill in the art:
An ordinary artisan in the area of drug development would have experience in synthesizing chemical compounds, such as a chemist. Screening of new drug candidates, while complex, is routine in the art. The process of finding new drugs that have in vitro activity against a particular biological target, (i.e., receptor, enzyme, etc.) is well known.
The breadth of the claims:
The scope of the claims involves compounds of formula (IIIa), shown below.
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Claim 17 is very broad in the number of variables and the options of substituents for each variable. There is an extremely large amount of hypothetical compounds included in claim 17.
The amount of direction provided, the presence or absence of working examples, and the quantity of experimentation necessary:
The specification provides the synthesis of approximately 32 unique compounds (more including all possible enantiomers). Synthesis methods are not taught in the specification to provide for the aforementioned variables to include all of the possible substituents listed in the claims. For example, there are no working examples of a compound of formula IIIa wherein there is an R4a or R4b group other than hydrogen along the [6,6]-ring fused core, or where G1, G2, G3, and G4 are anything other than carbon. It would be expected that varying the heteroatoms in the rings (e.g., G1-G4) would change the reactivity of the compounds, and therefore may require alternate synthesis methods. It would require one skilled in the art, such as a chemist, to perform thousands of reactions to determine which compounds of formula (IIIa) can be prepared and would likely require synthesis methods other than those provided in the specification. This is undue experimentation given the limited guidance and direction provided by Applicants.
Accordingly, the instant claims do not comply with the enablement requirement of 35 U.S.C. 112(a), since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
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, 6-14, 16, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Crew et al. (WO 2018/102725 A1, published June 7, 2018) (hereinafter “Crew”) and Arvinas press release (published December 14, 2020) (hereinafter “Arvinas press release”) in view of Wang et al. (WO 2022/187588 A1, published September 9, 2022, effectively filed March 4, 2021) (hereinfafter “Wang”).
Crew discloses tetrahydronaphthalene heterobifunctional PRTOAC molecules that target estrogen receptor (ER) for proteasome degradation, specifically Compound 411 (Figure 5, page 709), shown below:
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Reference compound 411 shares the preferred linker that is embodied in all examples of instant claim 16, as well as the preferred E3 ligase that is embodied in most examples of instant claim 16. The binding protein ligand of interest reads on most of instant genus formulae (I) and (II), with the key difference that instant R3a and R3b cannot be aryl or heteroaryl, whereas R3a and R3b are aryl in reference compound.
Wang also discloses heterobifunctional PROTAC molecules that target ER for proteasome-dependent degradation. Specifically, in Table 1, page 68, compound numbers E177-E179 (shown below), Wang discloses the following three PROTAC molecules that utilize a target protein ligand, linker unit, and E3 ligase (specifically, a cereblon E3 ligase):
E177: E178: E179:
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The reference molecules have a target protein ligand and linker unit that read on instant genus formulae (I) and (II), importantly, with a cycloalkyl group at R3a and R3b of instant formulae (I) and (II). Indeed, the reference target protein ligands can be found in instant claim 16 (page 7, row 1, col 2; page 9, row 5, col 2; page 12, row 6, col 2). However, Wang does not disclose a cereblon E3-ligase that reads on instant genus formulae (I) and (II).
Applicant would have been motivated to take known reference compound 411 of Crew and modify the instant R3a and R3b position with a cycloalkyl group taught by Wang. Arvinas press release reports that compound 411 had entered first-in-human Phase I/II clinical trial studies as lead clinical candidate ARV-471 as an oral PROTAC degrader that binds an E3 ubiquitin ligase and ER to directly trigger ubiquitination of ER and its subsequent proteasomal degradation. Arvinas press release reports:
“For ARV-471, interim Phase 1 data show potential for best-in-class safety and tolerability, estrogen receptor (ER) degradation superior to that previously reported for the current standard of care agent (fulvestrant), and robust efficacy signals in heavily pretreated patients with locally advanced or metastatic ER positive / HER2 negative (ER+/HER2-) breast cancer… Both ARV-471 and ARV-110 have been well tolerated, neither has reached a maximum tolerated dose, and the Phase 1 dose escalation trials for both programs continue. A Phase 1b combination trial of ARV-471 and Ibrance® (palbociclib) is expected to begin in December 2020, and a Phase 2 expansion cohort for ARV-471 is scheduled to begin in the first half of 2021.”
Therefore, it would have been prima facie obvious at the time of the effective filing date for one of ordinary skill to take known reference compound 411/ARV-471 of Crew and modify the instant R3a and R3b position with a cycloalkyl group taught by Wang. Applicant would have been motivated by the positive clinical trial data of Arvinas press release to arrive at compounds of instant genus (I) of claim 1 and species of instant claim 16 with a reasonable expectation of success.
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Since the dependent claims 2-3, 6-14, 16, and 20 do not resolve the obviousness rejection, they are similarly rejected.
Claim(s) 1-3, 6-14, 16-17, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Crew et al. (WO 2018/102725 A1, published June 7, 2018) (hereinafter “Crew”).
As described in the previous 35 U.S.C. 103 rejection, Crew discloses tetrahydronaphthalenes as selective estrogen receptor degraders for use in the treatment of breast cancer, as does instant application. The instant application differs from reference application in R3a and R3b: Crew discloses phenyl groups at this position, whereas instant application discloses benzyl groups (-CH2Ph) at these positions—methylene homologs of the compounds disclosed by Crew.
Crew also discloses aldehyde species l-[4-[(lR,2S)-6-hydroxy-2-phenyl-tetralin-lyl] phenyl]piperidine-4-carbaldehyde, shown below (para 0747-0748, page 483-484), used in the preparation of PROTAC molecules:
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Again, the difference between reference compound and compounds of instant claim 17 is the substituent at the instant R3a and R3b positions. Crew discloses phenyl groups at this position, whereas instant application discloses an alkyl group optionally substituted with aryl groups, so -CH2Ph as an option.
The Court of Customs and Patent Appeals (CCPA) has defined a homologous series as a family of chemically related compounds, the composition of which varies from member to member by a -CH2 (one atom of carbon and two hydrogen). In re Coes, Jr. (CCPA 1949) 173 F2d 1012, 81 USPQ 369. The Court of Appeals for the District of Columbia applied a broader definition and defined a homolog (homologue) as a member of a series of compounds in which each member differs from the next member by a constant number of atoms. Carr. Pats.v. Deutsche Gold-und-Sllber, etc. (CADC 1968) 397 F2d 656,157 USPQ 549.
The "Hass-Henze Doctrine" evolved from three CCPA cases, viz., In re Hass et al. (CCPA 1944) 141 F2d 122 and 127, 60 USPQ 544 and 548; and In re Henze (CCPA 1950) 181 F2d 198, 85 USPQ 261. In the Henze decision, the Court said:
"The nature of homologues and the close relationship the physical and chemical properties of one member of a series bears to adjacent members is such that a presumption of unpatentability arises against a claim directed to a composition of matter, the adjacent homologue of which is old in the art. The burden is on the applicant to rebut that presumption by a showing that the claimed compound possesses unobvious or unexpected beneficial properties not actually possessed by the prior art homologue. It is immaterial that the prior art homologue may not be recognized or known to be useful for the same purpose or to possess the same properties as the claimed compound. The CCPA concluded that because the characteristics normally possessed by members of a homologous series are principally the same, varying gradually from member to member, chemists knowing the properties of one member of a series would in general know what to expect in adjacent members so that a mere difference in degree is not the marked superiority which will ordinarily remove the unpatentability of adjacent homologues of old substances. Contra, where no use for the prior art compound is known. In re Stemniski (CCPA 1971) 444 F2d 581, 170 USPQ 343, and cases cited therein. Whether a compound is patentable over a prior art homologue or isomer is a question to be decided in each case. In re Hass et al., supra."
The 'Hass-Henze Doctrine" stands for the proposition that, "If that which appears at first blush to be obvious though new is shown by evidence not to be obvious then the evidence prevails over surmise or unsupported contention and rejection based on obviousness must fail." In re Papesch (CCPA 1963) 315 F2d 381, 137 USPQ 43, 48. The presumption that homologues are unpatentably obvious is an inference of fact, viz., that adjacent homologs are expected to have similar properties which places a 'burden of persuasion' on the applicant who asserted a contrary fact. In re Mills (CCPA 1960) 281 F2d 218, 126 USPQ 513.
Compounds that differ only by the presence of an extra methyl group are homologs. Homologs are of such close structural similarity that the disclosure of a compound renders prima facie obvious its homolog. The homolog is expected to be capable of preparation by the same method and to have the same properties. This expectation is then deemed the motivation for preparing homologs. Homologs are obvious even in the absence of a specific teaching to methylate, In re Wood 199 USPQ 137; In re Hoke 195 USPQ 148; In re Lohr 137 USPQ 548; In re Magerlein 202 USPQ 473; In re Wiechert 152 USPQ 249; Ex parte Henkel 130 USPQ 474; In re Fauque 121 USPQ 425; In re Druey 138 USPQ 39. In all of these cases, the close structural similarity of two compounds differing by only one (or two) methyl groups sufficed; no specific teaching to methylate was present or required. None of these cases has been overruled and indeed the examiner is unaware of any post-Lohr case in which motivation is required to put a methyl group on an old compound.
Given the small structural difference, the compounds of instant claims may only be regarded as nonobvious if the compounds of instant formulae (I) or (II) present unexpected effects of properties in relation to the compounds disclosed by Crew. No such effects or properties are indicated or supported in the instant application. Therefore, it would have been prima facie obvious at the time of the effective filing date for one of ordinary skill to take known reference compounds of Crew and make a structural methylene homolog to arrive at compounds of instant genus (I) of claim 1 and species of instant claim 16 with a reasonable expectation of success.
Since the dependent claims 2-3, 6-14, 16-17, and 20 do not resolve the obviousness rejection, they are similarly rejected. Claim 18 is objected to as being dependent upon rejected base claim 17.
CONCLUSION
Claims 1-3, 6-14, 16-17, and 20 are rejected.
Claim 18 is objected.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LUKE ALAN BORALSKY whose telephone number is (571)272-9746. The examiner can normally be reached Monday - Friday 7:30 am - 5:00 am.
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/L.A.B./Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624