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 .
Priority
The instant application, filed 02/28/2023, is a 371 filing of PCT/US21/48695, filed 09/01/2021, which claims domestic priority to provisional U.S. Application No. 63/073,256, filed 09/01/2020. Receipt is acknowledged of certified copies of papers required by 37 CFR § 1.55.
Amendments and Claim Status
The following amendment filed on 04/28/2026 is acknowledged and entered.
Claims 1, 2 are amended;
Claims 33-38 are added;
Claims 4-32 remain withdrawn according to 37 CFR § 1.142(b), as being drawn to a non-elected invention and species;
Claims 1-38 are pending and are under prosecution.
Response to arguments
Applicant’s arguments filed 04/28/2026 with respect to the objections to the specification, drawings, claims, and claim rejections under 35 U.S.C. §§ 112(a), 102 (a) (1/2), and 103 have been fully considered.
With respect to the objection to the specification, the replacement specification still continues to list compounds whose aspect ratio is not consistent among the rest of the list of compounds. The amendment to the specification is insufficient to overcome the rejection. Accordingly, the objection to the specification is amended to address the amended specification, and is hereby maintained.
With respect to the objection to the drawings, the amendment to Figures 2A, 2B, 4B, and 4C to display the data in a structural detail sufficient to understand the data is sufficient to overcome the objection. Accordingly, the objection to the drawings is hereby withdrawn.
With respect to the objections to claim 2, the correction of the NH2 substituents in the structure is sufficient to overcome the specific grounds of rejection. However, list of compounds includes a superscript in EO-11, which is inconsistent with the rest of the list compounds. Accordingly, the objection to the claim 2 is amended to address the amended compound list in the claim, and is hereby maintained.
With respect to the rejection of claims 1-3 under 35 U.S.C. § 112 (a) as failing to comply with the written description requirement, Applicant’s arguments have been fully considered and are persuasive. Accordingly, the rejection is hereby withdrawn.
With respect to the rejection of claims 2 under 35 U.S.C. § 112 (d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, Applicant’s amendments to claim 2, rewriting it as an independent claim, renders a rejection against said claim moot. Accordingly, the rejection is hereby withdrawn.
However, it is noted that new claim 37 continues to exhibit the same issues with lack of antecedent basis. Therefore, the same grounds of rejection is applied to newly added claim 37.
With respect to the rejection of claims 1-3 under 35 U.S.C. § 102 (a)(1) and (a)(2) as being anticipated by Zhi et al. (WO 2005118551 A2, published December 15, 2005), hereinafter Zhi, Applicant has amended the claim to include a proviso within claim 1, eliminating the prior art compound and disclosure from consideration as a prior art rejection on the grounds of anticipation. Furthermore, the amendment to re-write claim 2 as an independent claim, and the amendment to strike the instantly claimed compound EO-7 compound renders the rejection claim moot.
However, Erickson-Miller et al. (WO 2004096154 A2, published November 11, 2004), hereinafter Erickson-Miller, teaches a compound and pharmaceutical composition thereof which anticipates the limitations of amended claim 1 and 3 and newly added claims 33, 35, 36, and 38. This reference meets all the limitations of the compounds of the instant claims, and the rejection is not overcome by amendment. Accordingly, the rejection is amended to address the amended compound list in the claims, and is hereby maintained.
With respect to the rejection of claims 1-3 are rejected under 35 U.S.C. § 103 as being unpatentable over Zhi et al. (WO 2005118551 A2, published December 15, 2005), hereinafter Zhi, in view of Patani et al., (Chem Rev Volume 96, pg. 3147-3176, published December 19, 1996), hereinafter Patani, Applicant’s arguments with respect to the substituents R2 and R3 are convincing, and the original grounds of rejection is overcome. However, the combination of the same references continues to teach the elected species, and the rejection is hereby amended, and not overcome by rejection. Applicants arguments are herein addressed.
Applicant argues that Zhi discloses billions of potential variants at position Z, and does not single out a phenyl spacer substituted with a particular methyl group.
Applicant’s argument is found unpersuasive because the prior art compound clearly delineates a phenyl spacer, with n of the prior art Formula (I) equal to 0 which eliminates the alkyl spacer. Obviousness does not require that a compound be explicitly—the grounds of rejection is not made under anticipation. Furthermore, Zhi teaches wherein the phenyl group may be substituted (claim 1). Further still, Patani provides ample motivation to modify the compound by replacing a hydrogen with a methyl substituent. Therefore, in combination with the suggestion to substitute the phenyl group, and the disclosure of Patani teaches that methyl-hydride replacement is a common bioisostere it would have been obvious to a person of ordinary skill in the art to make such a substitution.
Applicant argues R2 and R3 are not substituents on “Z”, and are therefore separate from the spacer “Z.”
Applicant’s argument is found persuasive, and the rejection has been amended to remove this line of reasoning.
Applicant argues that the office has not provided a reason to replace the specific hydrogen on a specific carbon with a methyl group. Applicant further argues that the declaration by Dr. Gavathiotis demonstrates that compound 18 exhibited higher potency in comparison with the prior art compound.
Applicant’s argument is found unpersuasive because the comparative data exhibits only a moderate difference in potency. The difference in potency between the instantly claimed elected species and prior art compound is about a 1.6-fold change. An unexpected result would be a change of the order of several orders of magnitude. That is, the difference is, at best, modest. The slight increase in potency is well-within the range of ordinary variation between related compounds, and does not rise to the level of an unexpected result. Accordingly, the prima facie case of obviousness is not overcome by Applicant’s declaration.
Applicant claims that because Zhi does not exemplify the substituents on the phenyl ring (spacer Z), the structural features teach away from the claimed compounds.
Applicant’s argument is found unpersuasive because Zhi explicitly teaches wherein the phenyl may be substituted. Again, obviousness does not require that the prior art anticipate the instantly claimed. It is enough for the prior art to suggest such modification. According to claim 1, n (the linking component) may be 0, and Z (the spacer) may be a substituted phenyl. Patani teaches that hydride-methyl substitutions are well-known to artisans with ordinary skill in the art of drug discovery. This provides sufficient grounds for the obviousness rejection, and the rejection continues to stand on the same grounds.
Thus, all arguments presented by Applicants have been addressed and are found unpersuasive for the reasons presented herein and in the previous non-final rejection. Applicants are reminded that “attorney argument [is] not the kind of factual evidence that is required to rebut a prima facie case of obviousness.” In re Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997). The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965).
Status of the Claims
Claims 1-38 are pending in the instant application. Claims 4-32 were formerly withdrawn from further consideration pursuant to 37 CFR § 1.142(b), as being drawn to a non-elected invention and species. Claims 1-3 and new claims 33-38 read on an elected species and invention. Therefore, claims 1-3 and 33-38 are therefore under consideration in the instant application and are examined on the merits as such.
Drawings
The drawings filed on 04/28/2026 are found to be in compliance with 37 CFR §§ 1.121 and 1.84, and are hereby accepted.
Specification
The disclosure is objected to because of the following informalities:
The specification includes representations of the two-dimensional structures of the compounds of the instant claims that differ in size among one another. The aspect ratio of the 2D images is not consistent among the structures. Some compounds are in small print while others are printed to be larger (see the reproduced examples below on pages 4-8 and 19-23, below).
PNG
media_image1.png
577
527
media_image1.png
Greyscale
PNG
media_image2.png
376
284
media_image2.png
Greyscale
The compounds are not represented consistently, and appropriate correction is required.
Claim Objections
Claim 2 is objected to for designating EO-11 as having a superscript “11” while other compounds are listed as having the number in the compound name in regular script, as compared to EO-10 and EO-12, reproduced from the instant claims below. The arrow highlights the inconsistent insertion of a superscript in the naming designation of the instantly claimed compounds.
[AltContent: arrow]
PNG
media_image3.png
402
469
media_image3.png
Greyscale
Further regarding claim 2, the amended compounds are not consistent in size with respect to one another. In order for the objection to the withdrawn, the claims should list all compounds in a self-consistent format and size.
Claim 37 is objected to for including representations of the two-dimensional structures of the compounds of the instant claims that differ in size among one another. The aspect ratio of the 2D images is not consistent among the structures.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(d)
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 36 and 37 are 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. Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Claim 37 recites the limitation NO2 in position R3, in compound EO-3. This limitation contains subject matter that is not within the scope of the claim on which it depends, because the specific substituent is not defined within the limitations of R3 as recited in claim 1.
Further regarding claim 37 the claim recites the limitation -OH in position R2, in compound EO-10. This limitation contains subject matter that is not within the scope of the claim on which it depends, because the specific substituent is not defined within the limitations of R2 as recited in claim 1.
Further regarding claim 37, the claim recites the limitation
PNG
media_image4.png
115
143
media_image4.png
Greyscale
in position R4, in compound EO-25. This limitation contains subject matter that is not within the scope of the claim on which it depends, because the specific substituent is not defined within the limitations of R4 as recited in claim 1. Note that claim 36 also recites groups in position R4 that are not within the scope of claim 33.
Claim Rejections - 35 U.S.C. § 102
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 3, 33, 35, 36, and 38 are rejected under 35 U.S.C. § 102(a)(1) and (a)(2) as being anticipated by Erickson-Miller et al. (WO 2004096154 A2, published November 11, 2004), hereinafter Erickson-Miller.
The instant claims are drawn to a compound of Formula (I) and a pharmaceutical composition thereof.
Erickson-Miller teaches compounds which modulate the activity of thrombopoietin (Title). Specifically, Erickson-Miller discloses 3’-{N’-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hydrazino}-4’-hydroxybiphenyl-3-carboxylic acid (claim 10, page 45, lines 17 and 18), and a pharmaceutical composition thereof (page 5, lines 19-21, see Figure 1, below). Registry number 376594-07-9 is available as prior art as of 19 Dec 2001, the date it was indexed into the REGISTRY database. Registry number 376594-07-9 anticipates compounds of Formula (I) wherein:
Figure 1. Structural comparison of prior art compound and instantly claimed Formula (I)
PNG
media_image5.png
516
607
media_image5.png
Greyscale
Figure 1. a) CAS Registry Number: RN 376594-07-9 b) instantly claimed Formula (I)
1Y, Y2, Y3, Y4, 1X, X2, and R2 are H
R1 and X3 are OH
Z is CH3
R3 are H and CH3
See MPEP § 2128 “Printed Publications” as prior art. An electronic publication, including an on-line database or Internet publication, is considered to be a “printed publication” within the meaning of 35 U.S.C. § 102 (a) and (b) provided the publication was accessible to persons concerned with the art to which the document relates. In re Wyer, 655 F.2d 221, 227, 210 USPQ 790, 795 (CCPA 1981): since this date represents the date that each compound entered the REGISTRY database on STN, this represents the date that each compound was made accessible to the public.
It is further noted that for the purposes of determining if a reference is a “printed publication,” MPEP § 2128 (I) states the following:
A reference is proven to be a "printed publication" "upon a satisfactory showing that such document has been disseminated or otherwise made available to the extent that persons interested and ordinarily skilled in the subject matter or art, exercising reasonable diligence, can locate it." In re Wyer, 655 F.2d 221, 210 USPQ 790 (CCPA 1981) (quoting I.C.E. Corp. v. Armco Steel Corp., 250 F. Supp. 738, 743, 148 USPQ 537, 540 (SDNY 1966)) ("We agree that ‘printed publication’ should be approached as a unitary concept.
where “prior art disclosures…on an on-line database are considered to be publicly available as of the date the item was publicly posted.” Since each of the database entries above lists the date that each compound was entered into the on-line database, the compounds were made publicly available as of that date in each citation.
Accordingly, the instant claims are hereby rejected on the grounds of anticipation.
Claim Rejections - 35 U.S.C. § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-3, and 33-38 are rejected under 35 U.S.C. § 103 as being unpatentable over Zhi et al. (WO 2005118551 A2, published December 15, 2005), hereinafter Zhi, in view of Patani et al., (Chem Rev Volume 96, pg. 3147-3176, published December 19, 1996), hereinafter Patani.
The instant claims are drawn to a compound of Formula (I), elected to be compound EO-18, and a pharmaceutical composition thereof.
Zhi teaches compounds which modulate the activity of thrombopoietin (Title). Specifically, Zhi discloses compound 128, also known as CAS Registry Number: RN 871361-53-4. [Database Registry Chemical Abstracts Service, Columbus, Ohio, Accession No. RN 871361-53-4 , Entered STN: 06 Jan 2006]. (Example 28, page 67, claim 6), and a pharmaceutical composition thereof (claim 26, see Figure 2, below). Compound 128 renders obvious the elected species wherein,
Figure 2. Structural comparison of prior art compound and instant elected species
PNG
media_image6.png
338
481
media_image6.png
Greyscale
Figure 2. a) Zhi CAS Registry Number: RN 871361-53-4; b) Elected species, compound EO-18
1Y, Y2, Y3, Y4, 1X, X2, X3, and R2 are H
R1 is OH
Z is CH3
R3 are H and CH3
Zhi fails to teach the elected species, exactly. Specifically, Zhi fails to teach a compound wherein Y3 is CH3. However, Zhi teaches wherein Z in Formula (II) (right, below) is
PNG
media_image7.png
139
280
media_image7.png
Greyscale
a substituted aryl (claim 1) corresponding to substituent on the phenyl of the instant application.
Beyond this express teaching of substitution at the aryl position Z, a person of ordinary skill in the art would be expressly motivated to substitute methyl for hydrogen in the prior art compound, following the teachings of Patani, who teaches rational approaches in drug design, to develop novel and more-potent therapeutics.
Wherein Y3 is H in the prior art compound, and Y3 is CH3 in the elected species: this substitution is considered to be a classical bioisosteric replacement, well-known to the ordinary artisan in skilled in rational drug design. With respect to classical bioisosteres, Patani teaches that the substitution of hydrogen by methyl is one of the more commonly employed isosteric replacements (page 3152, section II, segment A, item 4 of Patani). This teaching is based on Grimm’s Hydride displacement law which describes how chemical groups can mimic each other, and is one of the most crucial lead modification tools in rational drug design. Therefore, a person having ordinary skill in the art prior to the effective filing date of the instant claims would be directly motivated to modify the compounds described by Zhi to include methyl in the place of hydrogen, as taught by Patani, on the Y3 substituent, in order to chemically modify the original compound, with a reasonable expectation of success.
Claims 1-3, and 33, and 35-37 are rejected under 35 U.S.C. § 103 as being unpatentable over Zhi et al. (WO 2005118551 A2, published December 15, 2005), hereinafter Zhi, in view of Zou et al., (BioTechniques, Volume 44, pages 377-384, published March 2008), hereinafter Zou.
The instant claims are drawn to a compound of Formula (I), elected to be compound EO-18, and a pharmaceutical composition thereof.
Zhi teaches compounds which modulate the activity of thrombopoietin (Title). Specifically, Zhi discloses compound 128, also known as CAS Registry Number: RN 871361-53-4. [Database Registry Chemical Abstracts Service, Columbus, Ohio, Accession No. RN 871361-53-4 , Entered STN: 06 Jan 2006]. (Example 28, page 67, claim 6), and a pharmaceutical composition thereof (see Figure 3, below). Compound 128 renders obvious the instantly claimed species EO-9 wherein,
Figure 3. Structural comparison of prior art compound and instant elected species
PNG
media_image8.png
390
548
media_image8.png
Greyscale
Figure 3. a) Zhi CAS Registry Number: RN 871361-53-4; b) Instantly claimed compound EO-9
1Y, Y2, Y3, Y4, 1X, X2, and X3 are H
R1 and R2 are OCH3
Z is CH3
R3 are H and CH3
Zhi fails to teach the instantly claimed compound exactly. Specifically, Zhi fails to teach wherein R1 is OCH3. However, Zhi teaches wherein R1 in Formula (II) (right, below) is
PNG
media_image7.png
139
280
media_image7.png
Greyscale
a CO2R10 and R10 is C1 alkyl (claim 1).
Beyond this express teaching that instantly claimed R1 may be CH3, a person of ordinary skill in the art would be expressly motivated to substitute methyl for hydrogen in the prior art compound, following the teachings of Zou, who teaches that methyl ester forms of carboxylic acid drugs improve cellular membrane penetration bioavailability (Abstract). Zou teaches that carboxylic acids are ionized at physiological pH, and therefore poorly membrane-permeable (page 377). Zou further teaches that neutral methyl esters can diffuse across cell membranes more readily, enabling higher intracellular drug concentrations, and potentially enhanced therapeutic potency (page 377). This common and well-known “pro-drug” strategy has been successfully applied to many known pharmaceuticals (page 377), and allows the ester to be hydrolyzed intracellularly by endogenous esterase is to regenerate the active acid form of the carboxylic acid compound (page 378).
Wherein R1 is H in the prior art compound, and R1 is CH3 in the instantly claimed compound EO-9: therefore, a person having ordinary skill in the art prior to the effective filing date of the instant claims would be directly motivated to modify the compounds described by Zhi to include methyl in the place of hydrogen on the R1 position, in order to create a more membrane-permeable pro-drug form of the prior art compound. The teachings of Zou expressly direct a person of ordinary skill in the art to cap the carboxylic acid of the prior art compound to create a methyl ester, which would provide reasonable expectation of success in creating a more effective drug compound, and result in compound EO-9, as instantly recited.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new grounds 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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sophia P. Hirakis whose telephone number is +1 (571) 272-0118. The examiner can normally be reached within the hours of 5:00 am to 5:00pm EST, Monday through Friday.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C. Milligan can be reached on +1 (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is +1 (571) 273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call +1 (800) 786-9199 (IN USA OR CANADA) or +1 (571) 272-1000.
/SOPHIA P HIRAKIS/Examiner, Art Unit 1623
/VALERIE RODRIGUEZ-GARCIA/Primary Examiner, Art Unit 1621
Prosecution Insights