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 October 10, 2023, is the national stage entry of PCT/KR2022/005210, filed April 11, 2022, which claims priority to an application filed in the Republic of Korea, KR 10-2021-0047170, filed on April 12, 2021. Receipt was acknowledged of certified copies of papers required by 37 CFR § 1.55. A certified translation of the priority application has not been received.
Information Disclosure Statement
The Information Disclosure Statement received on 10/10/2023 is acknowledged and found to be in compliance with the provisions of 37 CFR § 1.97. Accordingly, the Information Disclosure Statement has been considered.
Application History
Claims 1-14 were originally presented on 10/10/2023. The preliminary amendments to the claims also filed on 10/10/2023 were received and entered. Claims 12-14 were amended, and claims 15-38 were added. Claims 1-38 were pending and subject a requirement for restriction and election of species, mailed 03/09/2026. A response to the restriction requirement was received on 05/07/2026. No additional claims were added in the response.
Accordingly, claims 1-38 are pending.
Election/Restriction
Claims 1-38 were subject to a restriction/election requirement mailed 03/09/2026. Applicant’s election “without traverse, the Group VIII claims (Claims 4 and 11)”, in the reply filed on 05/07/2026, at 6, is acknowledged. See Group VIII defined in the 03/09/2026 Restriction Requirement, at 4:
PNG
media_image1.png
74
407
media_image1.png
Greyscale
03/09/2026 Restriction Requirement, at 4.
The restriction requirement for the Group VIII invention is deemed proper and is therefore made FINAL
Applicant’s provisional election to certain species of inventions with traverse is acknowledged. See reply filed on 05/07/2026 at 6-7. The examiner agrees that the species election is not necessary for the Group VIII invention. Accordingly, the election of species requirement is WITHDRAWN.
Status of Claims
Claims 1-38 are pending. Claims 1-3, 5-10, and 12-38 are withdrawn from further consideration pursuant to 37 CFR § 1.142(b), as being drawn to a non-elected invention. Therefore, claims 4 and 11 read on an elected invention and are therefore under consideration in the instant application.
Drawings Objections
The drawings are objected to because many of the figures are blurry and/or contain illegible text and markings. The examiner will permit Applicant to use its judgment to determine if select certain figures are of sufficient quality as to not require replacement. See, e.g., certain HPLC traces like Fig. 59. However, at present, all figures that have clear legibility issues are objected to and require replacement. Non-limiting examples of figures that require replacement are discussed below.
See, e.g., FIG. 1 in the file wrapper, reproduced below. The examiner cannot read the text in the figure. Further, the spectral features are not readable because the markings along the abscissa and ordinate are illegible. I.e., the examiner cannot see the abscissa markings between 5-10, denoting 6, 7, 8, and 9, or at any other step, making interpolation to certain spectral features burdensome if not impossible. This problem occurs in many figures. See FIG. 1:
PNG
media_image2.png
373
546
media_image2.png
Greyscale
FIG. 1.
See also, FIG. 25. The abscissa and ordinate are illegible.
PNG
media_image3.png
722
1072
media_image3.png
Greyscale
FIG. 25.
See also, FIG. 41. Several of the patterns are not readable due to the light shading used in the lines. This may be due to color figures submitted, rather than black and white figures. See, e.g., the top three patterns, FIG. 41:
PNG
media_image4.png
410
589
media_image4.png
Greyscale
FIG. 41.
See also, FIG. 49. The text is illegible:
PNG
media_image5.png
706
1046
media_image5.png
Greyscale
FIG. 49.
See also, FIG. 64, which depicts another problem common to several of the figures – box shading introduces barely legible text. The shading should be removed (see solvent indication), as well as correction of clear legibility problems with respect to the blurry text labelling each curve:
PNG
media_image6.png
403
588
media_image6.png
Greyscale
FIG. 64.
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
Claims 4 and 11 objected to because of the following informalities:
In view of the Restriction Requirement, claims 4 and 11 lack the referenced chemical structure of Chemical Formula 1 in the claim, which results in several antecedent basis issues. See, e.g., current claim 4.
PNG
media_image7.png
167
546
media_image7.png
Greyscale
Current claim 4.
The language in the preamble, emphasized here, “A crystalline form III of the sulfate of the compound of Chemical Formula 1 according to Claim 1”, requires revisions. The examiner recommends that Applicant amend claim 4 to change the emphasized “the sulfate” to “a sulfate”, and “the compound” to “a compound”, and provide the chemical structure of Chemical Formula 1 directly within claim 4. Further, rather than raise a separate 112(b) rejection, the examiner currently objects to the recitation of “the crystalline form” in the wherein clause, as the language is potentially vague. The wherein clause should clearly point to “the crystalline form III”, and not just “the crystalline form”.
For example, the following language appears to resolve these issues: “A crystalline form III of a sulfate of a compound of Chemical Formula I,
PNG
media_image8.png
155
239
media_image8.png
Greyscale
,
wherein, the crystalline form III …”.
The examiner cautions that directly copying the language from claim 1 into claim 4 will result in the issue identified in the below annotated claim 1:
PNG
media_image9.png
218
695
media_image9.png
Greyscale
The above punction issue appears in claim 11 as well. Applicant is advised to ensure that amendments to claim 4 clearly follow through to claim 11.
Claim amendments must be consistent with the Restriction Requirement.
Appropriate correction is required.
Claim Rejections - 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.
Claim 4 Does Not Comply with the Enablement Requirement
Claim 4 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Determining compliance with the enablement requirement is measured by analyzing the so called “Wands factors to assess whether any necessary experimentation required by the specification is ‘reasonable’ or is ‘undue.’” See MPEP 2164.01(a). The examiner finds that the weight of the Wands factors assessed for claim 4 establishes that undue experimentation would have been needed to make and use the full scope of the claimed invention.
The Claim
Claim 4 is reproduced below:
PNG
media_image7.png
167
546
media_image7.png
Greyscale
Claim 4.
Initial Discussion
Before proceeding through the traditional enablement analysis, it is helpful to directly identify the problem with claim 4. There are simply too many overlapping peaks between the various crystalline forms of the active that one of skill in the art to which it pertains would not be able to identify crystalline form III based upon four XRPD peaks. It appears that either an orthogonal measurement is required to identify crystalline form III (e.g., DSC), and/or more specific conditions are necessary to identify crystalline form III by XRPD.
Envision a technician at a lab measuring powder samples obtained from a customs agent. Such a technician normally screens powders by XRPD to obtain a quick fingerprint readout for sample identification. Further, such a technician is one of skill in the art to which it pertains, given that he is tasked with identifying unknown powder samples.
The technician has 16 peaks to identify, and only 4 must match within a standard deviation of ±0.2θ. See claim 4. The Specification gives the 25 “characteristic” XRPD peaks for Crystalline form III of the active claimed in claim 4. See Specification at 46, Table 17 (annotated below, following page, to highlight the peaks recited in claim 4). Now compare the 10 “characteristic” XRPD peaks for Crystalline form II of the active, Specification at 45, Table 16 (annotated below to highlight the peaks recited in claim 4).
The six highlighted “characteristic” form II peaks overlap within a standard deviation of ±0.2θ with peaks used to ID form III.
PNG
media_image10.png
707
808
media_image10.png
Greyscale
PNG
media_image11.png
366
796
media_image11.png
Greyscale
Annotated Table 17 (left) and Table 16 (right).
Crystalline form II is exemplary. The same issue appears to arise with other crystalline forms. See, e.g., Specification at 43-44, Table 15 (providing “characteristic” peaks for form I that also overlap).
Now, turning to the traditional enablement analysis, the examiner finds as follows:
1. The breadth of the claim
While the breadth of the claim, at first glance, is to a single crystalline form of an active ingredient used in medicine, its breadth in fact encompasses many crystalline forms of the active ingredient. Each crystalline form has a unique crystalline geometry that impacts certain properties of the crystal, such as its solubility. The current claim encompasses many crystalline forms, and not just crystalline form III.
Accordingly, the breadth of the claim exceeds what the Specification enables for identifying Crystalline form III of the active.
2. The nature of the invention and state of the prior art
The nature of the invention of claim 4 relates to the identification of powder samples by routine XRPD measurements. The state of the prior art establishes that this was a routine screening process used by many technicians to quickly identify powder samples. See, e.g., Witkowski 2016, attached hereto, which provides a quick background regarding the use of XRPD to identify counterfeit pharmaceuticals.1
Accordingly, the nature of the invention and state of the prior art requires minimal experimentation to quickly identify powder samples.
3. The level of one of ordinary skill
The level of one of ordinary skill in the art is that of a technician. Not to disparage technicians, but technicians are not nearly as skilled as the inventors of the instant subject matter. Technicians may have but one instrument to process XRPD samples on, and little time for experimentation.
Often, such technicians rely upon an orthogonal measurement to identify an unknown sample. See, e.g., Jendrzejewska 2018, discussing the use of DSC as an orthogonal measurement to identify counterfeit drugs.2
Accordingly, the level of skill in the art is that of a technician, tasked with rapid identification of samples and left with minimal time for experimentation.
4. The level of predictability in the art and the amount of direction provided by the inventor
The level of predictability in the art of API identification requires certain, specific conditions for sample measurement. APIs, particularly those that are polymorphic, often degrade, absorb water, or otherwise produce complex signals complicated by overlapping peaks. This is clearly exemplified in the discussion of the XRPD patterns of the instant crystalline forms II and III of the instant API, Tables 16 and 17.
The amount of direction in the specification indeed provides a protocol for sample measurement and identification. See, e.g., Specification at 46, Table 17, discussed above. See also, Specification at 20-21, excerpted below, providing a protocol for sample measurement, which includes XRPD, DSC, and TGA:
PNG
media_image12.png
637
834
media_image12.png
Greyscale
PNG
media_image13.png
175
825
media_image13.png
Greyscale
Specification at 20-21.
Notably, the protocol for XRPD measurement includes certain critical measurement parameters that are omitted in the current claim 4, e.g., the source of the radiation used to measure the sample, rotational speed and angles.
Moreover, the aforementioned Table 17 appears in the specification under the heading “Example 6-3: Identification of Crystalline form III”, see Specification at 46-47. In this section, which immediately follows the discussion of the XRPD pattern, the Specification explains that orthogonal measurements, such as HPLC, DSC, and TGA, were used for identification of crystalline form III. See Specification at 47:
PNG
media_image14.png
249
861
media_image14.png
Greyscale
Specification at 47.
See also, Specification at 43-45, wherein it states on page 44 that TGA was used “[t]o identify” Crystalline form I. It follows from the specification itself that an orthogonal measurement is required to identify a crystalline form of the active claimed. Alternatively, identification requires more XRPD peaks than currently claimed, for clear enablement.
Accordingly, the breadth of the invention as claimed exceeds the amount of direction in the provided in the specification. There appears to be no clear way to identify a crystalline form of the active with four XRPD peaks.
5. The existence of working examples
The specification provides sufficient working examples to identify crystalline form III of the active. The claim, however, is drawn to many other crystalline forms of the active than the crystalline form III.
Accordingly, while the specification provides working examples, the working examples are not commensurate with the breadth of the claim.
6. The quantity of experimentation needed to make or use the invention based on the disclosure
It appears it could take an infinite amount of experimentation to identify a crystalline form of the active based upon four XRPD peaks. In view of the discussion of Tables 16 and 17 alone, an unfortunate technician of skill in the art tasked with identifying powdered samples of crystalline forms of the active could spend a lifetime repeatedly measuring XRPD patterns, all to never uncover the true identity of the crystalline form present in the sample.
The weight of the Wands factors establishes undue experimentation for claim 4
The examiner finds that the weight of the Wands factors assessed for claim 4 establishes that undue experimentation would have been needed to make and use the full scope of the claimed invention.
Each factor weighs heavily towards undue experimentation being required to make and use the full scope of the claimed invention.
Accordingly, claim 4 is rejected as it does not comply with the enablement requirement.
The examiner recommends that Applicant either require more XRPD peaks that clearly identify the crystalline form III of the active, taking into account the fact that the actives exhibit strong peak overlap within the standard of error, and include certain measurement parameters such as the identification protocol, or require that the claim recite matching a select number of XRPD peaks and an orthogonal measurement. The latter appears to be preferred, as such identification is enabled by the specification. Further, in view of the objections to the drawings, clearer drawings may help resolve some of these underlying issues regarding sample identification.
Claim 11 Does Not Comply with the Enablement Requirement
Claim 11 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The examiner finds that the weight of the Wands factors assessed for claim 11 establishes that undue experimentation would have been needed to make and use the full scope of the claimed invention.
The Claim
Claim 11 is a product by process claim, seeking protection for a method of preparing the crystalline form III of the active. It is reproduced below. See claim 11:
PNG
media_image15.png
312
659
media_image15.png
Greyscale
Claim 11.
Initial Discussion
The enablement issue regarding claim 11 requires first briefly discussing the preparation of crystalline form III of the active. Its preparation is generally outlined in the Specification under Examples 6-3, 4-4, 4-1, and 5-8. Primarily, Examples 4-4 and 4-1 discuss its preparation. See Examples 6-3, 4-4, and 4-1 excerpted below, from Specification at 46, 34, and 33-34, respectively:
PNG
media_image16.png
127
545
media_image16.png
Greyscale
PNG
media_image17.png
191
532
media_image17.png
Greyscale
PNG
media_image18.png
347
565
media_image18.png
Greyscale
Excerpted Examples 6-3, 4-4, and 4-1.
See also, FIG. 62, which provides the XRPD pattern of the crystalline form III prepared as described in the specification, which is reproduced below, and note the solvent system labeled above Pattern 2-III (MeOH/H2O 9/1 ratio):
PNG
media_image19.png
540
820
media_image19.png
Greyscale
FIG. 62.
However, now see Specification at 36-37 (discussing other methods of preparing the crystalline form III, wherein the crystalline form III is subjected to a routine slurry experiment). In particular, see Table 12, excerpted and annotated below.
PNG
media_image20.png
395
684
media_image20.png
Greyscale
Specification at 37, Annotated Table 12.
Surprisingly, crystalline form III appears to be quite stable, despite being subjected to different solvents and stress test conditions (e.g., 50 ⁰C at 4 weeks). However, as soon as water is introduced, the crystal changes form (compare results in acetone, to MeOH/water (1:1), for example). The introduction of water appears to destroy the stability of the crystalline form (see, e.g., stability results for 50 ⁰C at 4 weeks for the MeOH/water (1:1) entry).
See also, FIG. 39, reproduced below, that shows the difference between the forms III and V, which indeed are quite different:
PNG
media_image21.png
522
800
media_image21.png
Greyscale
FIG. 39.
Now, turning to the traditional enablement analysis, the examiner finds as follows:
1. The breadth of the claim
While the breadth of the claim, at first glance, is to a simple, relatively routine procedure for preparing a specific polymorphic form of an active ingredient used in medicine, its breadth in fact encompasses the preparation of an uncertain amount of other polymorphic forms of the active ingredient.
Accordingly, the breadth of the claim exceeds what the Specification enables for preparing Crystalline form III of the active.
2. The nature of the invention and state of the prior art
The nature of the invention of claim 11 relates to the preparation of a crystalline form of a small molecule organic compound, in this case, a sulfate of an active ingredient used in medicine. The API, in its free-base form, is commonly known as Necrox 7, and has an indole chemical scaffold. The state of the prior art establishes that preparing crystalline forms of small molecule organic compounds, in particular those that bear an indole chemical scaffold, were relatively routine procedures.
For example, see US’7913 at 1, left column (providing the chemical structure of a related indole used medicinally):
PNG
media_image22.png
174
251
media_image22.png
Greyscale
,
and see US’791, at 12, Example 5 (describing a routine experiment for preparing a crystalline form of the active described in US’791 using conditions that are essentially identical to those described in the instant claim 11):
PNG
media_image23.png
256
414
media_image23.png
Greyscale
US’791, at 12, Example 5.
Further, crystalline procedures are routine and are taught in general chemistry labs to students. Following crystallization procedures requires only basic skills in chemistry.
Accordingly, the nature of the invention and state of the prior art requires minimal experimentation to quickly follow a procedure to achieve consistent results. Consistency in API preparation is critical for medical applications, where purity standards are high as required by regulatory agencies.
3. The level of one of ordinary skill
The level of one of ordinary skill in the art is again that of a technician. Not to disparage technicians, but technicians are not nearly as skilled as the inventors of the instant subject matter. Technicians may have limited apparatuses to work with, and little time for experimentation to adjust crystallization conditions.
Accordingly, the level of skill in the art is that of a technician, tasked with rapid preparation of samples and left with minimal time for experimentation.
4. The level of predictability in the art and the amount of direction provided by the inventor
The level of predictability in the art of polymorphic API preparation requires certain, specific conditions for API production. As discussed earlier with respect to claim 4, APIs, particularly those that are polymorphic, often degrade, absorb water, or otherwise produce complex signals complicated by overlapping peaks. This is clearly exemplified in the discussion of the above slurry experiments, wherein the introduction of additional amounts of water destroys the stable polymorphic crystalline form III.
The amount of direction in the specification indeed provides a protocol for preparing crystalline form III. See, e.g., the discussion above several pages back, Example 4-4. The preparation of crystalline form III requires certain conditions, including a precise mixture of 9:1 methanol to water.
Notably, the protocol recited in claim 11 lacks such certain conditions.
Accordingly, the breadth of the invention as claimed exceeds the amount of direction in the provided in the specification. There appears to be no clear way prepare crystalline form III by following the procedure recited in the claim.
5. The existence of working examples
The specification provides sufficient working examples to prepare crystalline form III of the active. The claim, however, is drawn to the preparation of many other crystalline forms of the active than the crystalline form III.
Accordingly, while the specification provides working examples, the working examples are not commensurate with the breadth of the claim.
6. The quantity of experimentation needed to make or use the invention based on the disclosure
It appears that it would take an inordinate amount of experimentation to prepare crystalline form III of the active by following the recited procedure. The technician would be required to constantly adjust the solvent system, measure XRPD, and find that the desired crystalline form III of the active did not form. The flummoxed technician would have report to his supervisor that his experiments unfortunately failed again. Perhaps some crystalline form III would form using whatever amount of water was mixed with methanol as permitted by the claim, but not a sufficient amount to meet the purity standards required for medicinal use of the active.
The weight of the Wands factors establishes undue experimentation for claim 11
The examiner finds that the weight of the Wands factors assessed for claim 11 establishes that undue experimentation would have been needed to make and use the full scope of the claimed invention.
Each factor weighs towards undue experimentation being required to make and use the full scope of the claimed invention.
Accordingly, claim 11 is rejected as it does not comply with the enablement requirement.
The examiner recommends that Applicant amend the claim in such a way that following the recited procedure results in the crystalline form III of the active. The crystalline forms produced by the recited process are beyond the scope of what is enabled for crystalline form III of the active. Simply adding the 9:1 ratio of methanol to water appears to resolve the enablement issue.
Prior art Cited but not Applied
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Kim, Soon Ha, et al., U.S. Patent No. US 12649730 B2, published 2026-06-09, hereinafter “US’730”.
Claim 1 of US’730 is deceptively similar to the instant claim 4. See, e.g., US’730, at col. 36, claim 1, reproduced below:
PNG
media_image24.png
400
403
media_image24.png
Greyscale
US’730, claim 1.
Essentially the same API is recited, and the peaks generally overlap within the standard of deviation. The difference between the claims, however, ends up being that the instant claims are drawn to a polymorphic form of a sulfate of the API, whereas US’730 claims a polymorphic form of the free base. The examiner thought it was worthwhile to draw the distinction, in view of the claim possibly being mistaken as a statutory double patenting reference.
However, the examiner notes that the inventors between the two applications are slightly different, despite closely overlapping subject matter. If Applicant needs to correct inventorship in the instant application, the examiner recommends that Applicant address that issue promptly.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Christopher Evan Redwood whose telephone number is (571) 272-8882. The examiner can normally be reached Monday - Friday 6:15 AM - 4:45 PM.
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, Jeffrey S. Lundgren can be reached at 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 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 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/C.E.R./ Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/ Supervisory Patent Examiner, Art Unit 1629
1 Witkowski, Mark R., et al., “B196 X-Ray Powder Diffraction (XRPD) Method Development and Validation for the Identification of Counterfeit Pharmaceuticals”, 2016, available online at https://www.aafs.org/research/x-ray-powder-diffraction-xrpd-method-development-and-validation-identification-counterfeit, hereinafter “Witkowski 2016”.
2 Jendrzejewska, Izabela, et al. "Application of X-ray powder diffraction and differential scanning calorimetry for identification of counterfeit drugs." Monatshefte für Chemie-Chemical Monthly 149.5 (2018): 977-985, hereinafter “Jendrzejewska 2018”.
3 Chen, Z., et al., “EGFR INHIBITOR FREE BASE OR ACID SALT POLYCRYSTALLINE FORM, PREPARATION METHOD THEREFOR, AND APPLICATION”, U.S. Patent Application No. US 20190077791 A1, published 2019-03-14, hereinafter “US’791”.
Prosecution Insights