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 .
Election/Restriction
1. Restriction to one of the following inventions is required under 35 U.S.C. 121:
I. Claims 1-16, are drawn to a method for treating or preventing amblyopia, classified in
A61P 27/10.
II. Claims 17-20, are drawn to the use of a CCKBR agonist in the manufacture of a
medicament, classified in A61K 38/00, A61P 27/02.
Examiner’s Note: Claims 17-20 are drawn to the use of a CCKBR agonist in the manufacture of a
Medicament. Use claims are not a statutory class of invention under US practice. Applicants are advised to amend the claim to be drawn to one of the four US statutory class of invention (i.e., device, apparatus, manufacture, or composition). Once amended, the claim would be added to an existing group or to a new group. Please see MPEP § 2173.05(q) regarding “use” claims. To advance prosecution, the Examiner is interpreting the use claims as method of making a medicament.
The inventions are independent or distinct, each from the other because:
Inventions I and II are directed to related processes. The related inventions are distinct if: (1) the inventions as claimed are either not capable of use together or can have a materially different design, mode of operation, function, or effect; (2) the inventions do not overlap in scope, i.e., are mutually exclusive; and (3) the inventions as claimed are not obvious variants. See MPEP § 806.05(j). In the instant case, the inventions as claimed have a materially different design, mode of operation, function and effect. In the instant case, Group I is a method of use (i.e., treating or preventing amblyopia) and Group II is a method of making a medicament. Furthermore, the inventions as claimed do not encompass overlapping subject matter and there is nothing of record to show them to be obvious variants.
Restriction for examination purposes as indicated is proper because all the inventions listed in this action are independent or distinct for the reasons given above and there would be a serious search and/or examination burden if restriction were not required because one or more of the following reasons apply:
(A) Separate classification thereof: This shows that each invention has attained recognition in the art as a separate subject for inventive effort, and also a separate field of search. Patents need not be cited to show separate classification.
(B) A separate status in the art when they are classifiable together: Even though they are classified together, each invention can be shown to have formed a separate subject for inventive effort when the examiner can show a recognition of separate inventive effort by inventors. Separate status in the art may be shown by citing patents which are evidence of such separate status, and also of a separate field of search.
(C) A different field of search: Where it is necessary to search for one of the inventions in a manner that is not likely to result in finding art pertinent to the other invention(s) (e.g., searching different classes/subclasses or electronic resources, or employing different search queries), a different field of search is shown, even though the two are classified together. The indicated different field of search must in fact be pertinent to the type of subject matter covered by the claims. Patents need not be cited to show different fields of search.
In the instant case, different search queries would have to be performed since the inventions are different and distinct given that the inventions are classified under different classification schemes.
Applicant is advised that the reply to this requirement to be complete must include (i) an election of an invention to be examined even though the requirement may be traversed (37 CFR 1.143) and (ii) identification of the claims encompassing the elected invention.
The election of an invention may be made with or without traverse. To reserve a right to
petition, the election must be made with traverse. If the reply does not distinctly and specifically point out supposed errors in the restriction requirement, the election shall be treated as an election without traverse. Traversal must be presented at the time of election in order to be considered timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are added after the election, applicant must indicate which of these claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct,
applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
2. During a telephone conversation with Nathan Braswell on December 8th, 2023 a provisional election was made without traverse to prosecute the invention of Group I, claims 1-16. Affirmation of this election must be made by applicant in replying to this Office action. Claims 17-20 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
4. Applicant is reminded that upon the cancelation of claims to a non-elected invention, the
inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
5. The examiner has required restriction between product or apparatus claims and process claims. Where applicant elects claims directed to the product/apparatus, and all product/apparatus claims are subsequently found allowable, withdrawn process claims that include all the limitations of the allowable product/apparatus claims should be considered for rejoinder. All claims directed to a nonelected process invention must include all the limitations of an allowable product/apparatus claim for that process invention to be rejoined.
In the event of rejoinder, the requirement for restriction between the product/apparatus claims and the rejoined process claims will be withdrawn, and the rejoined process claims will be fully examined for patentability in accordance with 37 CFR 1.104. Thus, to be allowable, the rejoined claims must meet all criteria for patentability including the requirements of 35 U.S.C. 101, 102, 103 and 112. Until all claims to the elected product/apparatus are found allowable, an otherwise proper restriction requirement between product/apparatus claims and process claims may be maintained. Withdrawn process claims that are not commensurate in scope with an allowable product/apparatus claim will not be rejoined. See MPEP § 821.04. Additionally, in order for rejoinder to occur, applicant is advised that the process claims should be amended during prosecution to require the limitations of the product/apparatus claims. Failure to do so may result in no rejoinder. Further, note that the prohibition against double patenting rejections of 35 U.S.C. 121 does not apply where the restriction requirement is withdrawn by the examiner before the patent issues. See MPEP § 804.01.
Claims17-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention. A provisional election was made without traverse during a telephone conversation on December 8th 2023.
Status of Claims
Claims 1-20 were originally filed on February 1st 2023.
The amendment filed on November 5th 2024, cancelled claims 6 and 14; and amended claims 1, 3 and 9.
The amendment filed on June 2nd 2025, amended claims 3 and 9.
The amendment filed on June 17th 2026, amended claim 3.
Claims 1-5, 7-13, and 15-20 are currently pending and claims 1-5, 7-13 and 15-16 are under consideration.
Priority
The effective filing date of the instant application is 02/01/2023.
Claim Interpretation
For purposes of applying prior art, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation set forth below, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
For claim 1, regarding “agonist,” it is noted that the instant specification does not define what constitutes “agonist.” Rather, the instant specification recites that the CCKBR agonist is selected from the group of CCK8s, CCK4, 3rl and a combination thereof (see instant specification, pg. 5, para[0035]). Pursuant to MPEP 2111.01, under a broadest reasonable interpretation, words of the claim must be given their plain meaning, unless such meaning is inconsistent with the specification. The plain meaning of a term means the ordinary and customary meaning given to the term by those of ordinary skill in the art at the time of the invention. The Merriam Webster Dictionary defines “agonist” as a chemical substance capable of combining with a specific receptor on a cell and initiating the same reaction or activity typically produced by the binding endogenous substance (see Meriam Webster Dictionary, “Agonist,” available at https://www.merriam-webster.com/dictionary/agonist accessed on 05/21/2024). As such, the Examiner is interpreting the scope of “agonist” as a substance capable of combining with a specific receptor on a cell and mimicking the same reaction or response as the endogenous substance.
Although the instant specification only teaches three examples of CCKBR agonist (i.e., CCK8s, CCK4 and 3rl), the prior art identifies a representative number of cholecystokinin receptor B that exhibit the function of being agonist. CN113929737A and the English version equivalent WO2023/065716A1 (hereinafter ‘716, which will be cited in the 103 rejection below) teach a polypeptide that its use as a CCK receptor agonist/antagonist (see ’716, pg. 1, paragraph 1). The polypeptide has a high agonistic/antagonistic activity on CCK receptors (see ‘716, pg. 2, first paragraph). ‘716 teaches Table 1 which depicts compounds HT-1 to HT-292 and their respective agonistic activity (%) at 10 µM (see ‘716, Table 1, pgs. 12-79). As such, given the pre-existing knowledge in the art demonstrating a representative number of species that fall within the claimed genus of cholecystokinin receptor B (CCKBR) that would exhibit the function of agonist, an ordinary skilled artisan would have put one in possession of the genus of a CCKBR agonist. Thus, an ordinary skilled artisan would conclude that the applicant was in possession of the claimed genus at the time the application was filed.
For claim 9, regarding “a method of regaining or improving visual acuity by administrating a therapeutically effective amount of CCKBR agonist to a subject in need thereof.” The Examiner is interpreting the patient population (i.e., a subject in need thereof) as encompassing any subject suffering from any eye condition (i.e., cataracts, glaucoma, macular degeneration, etc.) that reduces vision either temporality or permanent.
For claim 11, regarding “about,” it is noted that the instant specification does not define what constitutes “about” in relation to the frequency to which the CCKBR agonist is administrated. The Examiner is interpreting “about” as encompassing administrating the CCKCR agonist in a range of 1 dose per week up to 1 dose daily or seven times a week. Therefore “about 4 times a week” includes daily or once a day or every other day.
Response to Arguments
1. Applicants' arguments, see Response, filed 06/17/2026, with respect to 35 U.S.C. 112(b) rejection as being indefinite for failing to particularly point out and distinctly claim the subject matter, have been fully considered but are not persuasive. The 35 U.S.C. 112(b) rejection to claim 3 has been maintained.
2. Applicants' arguments, see Response, filed 06/17/2026, with respect to 35 U.S.C. 112(a) rejection as failing to comply with the written description requirement (i.e., new matter), have been fully considered but are not persuasive. The 35 U.S.C. 112(a) rejection to claim 3 has been maintained.
3. Applicants' arguments, see Response, filed 06/17/2026, with respect to 35 U.S.C. 103 rejection as being unpatentable, have been fully considered but are not persuasive. The 35 U.S.C. 103 rejection to claims 1-5, 7-13 and 15-16 has been maintained.
Maintained/Modified Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112
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.
1. Claim 3 is 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. Instant claim 3 was amended to recite: “wherein the CCKBR agonist is administrated in a range of seven days, and a single dose is administered every other day for a total of at least four doses.” However, the newly added limitation renders the claim indefinite because the phrase “for a total of at least four doses” indicates that the total number of doses administered in seven days are four or more than four. Thus, claim 3 is internally inconsistent because a single dose administered every other day in a time span of 7 days, cannot result in a total of more than four administered doses. As such, one of ordinary skill in the art would be unable to ascertain the meets and bounds of the invention with regards to the administration parameters of the CCKBR agonist. In order to advance prosecution, the frequency of administration will be interpreted as: a single dose every other day, for seven days.
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.
2. Claim 3 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
As discussed above in the 35 U.S.C. 112 (b) rejection, instant claim 3 was amended to recite “…in a range of seven days, and a single dose is administered every other day for a total of at least four doses.” Applicants stated that “all amendments have proper basis and that no new matter is added” (see pg. 5 of 9, Remarks filed on 06/17/2026). However, after carefully reviewing the evidence provided in the specification, it is noted that Example 1 at pp. 9, para[0050] provides evidence of two different drug dose frequencies that supports administering “a total of at least 4 doses”. For instance lines 22-23 at pg. 9, para[0050] recites a) 4 doses on alternate days for 7 days; and b) 8 doses on alternate days for 14 days. As best understood, dose frequency a) is being interpreted as administering 4 doses on day 1; 4 doses on day 3; 4 doses on day 5; and 4 doses on day 7; thereby corresponding to a total of at least four doses, wherein the phrase at least corresponds to four or more than four. The same is true for dose frequency b): 8 doses on day 1, 8 doses on day 3, etc. Therefore, the instant specification fails to provide evidence to support the newly added amendment, wherein in a range of 7 days, a single dose is administered every other day for a total of at least four doses. As such, the instantly claimed method has not been adequately supported.
Claim Rejections - 35 USC § 103
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.
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness (Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, 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).
3. Claims 1-5, 7-13, 15 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Chung et al., 2009. Brain Research 1282, pp. 10-19 (herein after “Chung et al.”) in view of Olsen et al., 2012. Nature., vol. 483, pp. 1-8 (herein after “Olsen et al.”); Li et al., 2014. Cell Research, 307-330 (herein after “Li et al.”), as evidenced by Puderbaugh et al. Neuroplasticity. [Updated 2023 May 1]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK557811/ (herein after “Puderbaugh et al.”); and English version equivalent of CN113929737A published on January 14th, 2022 (WO2023/065716A1 English version equivalent published on April 27th, 2023 (herein after ‘716)).
Regarding claims 1 and 9, Chung et al. examined the actions of cholecystokinin (CCK) action agonists CCK8S and CCK4 on layer 6b neocortical neurons using whole-cell patch clamp recording techniques (see pg. 10, abstract). It was found that the general CCK receptor agonist CCK8S (sulfated CCK octapeptide) strongly depolarized the neurons, and this action persisted in the presence of tetrodotoxin (i.e., voltage-dependent sodium channel blocker), across the concentration range tested (0.125-2.5µM), suggesting that the CCK8S agonists acts on postsynaptic CCK receptors (see pg. 12, left column last paragraph). It was also found that the excitatory actions of the general CCK8S agonist were mimicked by the selective CCKB receptor agonist CCK4 (see pg. 10, abstract, and pg. 12, left column, last paragraph). Although CCK was initially found in gut and later widespread within the brain, CCK receptors are localized in both deep layers of neocortex as well as thalamus (see pg. 11, right column, first full paragraph).
Chung et al. report that CCK acting at CCKB receptors, selectively depolarizes layer 6b projection neurons by suppressing a leak K+ current thus increasing the excitability of these deep layer neurons as well as potentially facilitating excitatory transmission through this circuit, ultimately influencing thalamocortical circuit activity by modulating the corticothalamic feedback (see pg. 12, left column, first full paragraph). Since layer 6b neurons give rise to both corticothalamic and corticocortical projections, and because CCK8S depolarize all layer 6b neurons, both circuits are likely affected (see pg. 16, left column, second paragraph). According to the literature reviewed by Chung et al., layer 6 inputs have been referred to as modulatory in that these inputs may play an important role in setting the gain, or sensitivity, of neurons to afferent inputs (see pg. 16, right column, second paragraph). Corticothalamic input from layer 6 is hypothesized to provide a modulatory input to first- and higher-order thalamic nuclei while higher order thalamic nuclei receive driver input from layer 5 corticothalamic neurons. Functionally, such an arrangement could serve as a means for interconnecting different cortical areas (see pg. 16, right column, second paragraph).
Therefore, Chung et al.’ work demonstrate that layer 6 neocortical neurons when exposed to the general CCK receptor agonist CCK8S and the specific CCKB receptor agonist CCK4 at a concentration range of 0.125-2.5µM, exhibit an increase in excitability which ultimately translate to other circuits and/or neocortical areas that modulate the gain or sensitivity of neurons to afferent inputs.
However, Chung et al. do not expressly teach a method for treating amblyopia by administrating a therapeutically effective amount of CCKBR agonist to a subject in need thereof, as recited in claim 1; nor a method of regaining or improving visual acuity of a subject experiencing amblyopia and reduced visual acuity amblyopia by administrating a therapeutically effective amount of CCKBR agonist the subject, as recited in claim 9.
Olsen et al. teach that sensory information spreads through six different horizontal neuronal layers that are interconnected by vertical axonal projections and it is believed that through these projections layers can influence each other’s response to sensory stimuli (see pg. 47, abstract). Olsen et al. show that layer six in the primary visual cortex of the mouse has a crucial role in controlling the gain of visually evoked activity in neurons of the upper layers without changing their tuning to orientation (see pg. 47, abstract). Additionally that the gain modulation results from the coordinated action of layer six intracortical projections to superficial layers and deep projections to the thalamus, with a substantial role of the intracortical circuit (see pg. 47, abstract). Olsen et al.’s work establishes layer six as a major mediator of cortical gain modulation and suggests that it could be a node through which convergent inputs from several brain areas can regulate the earliest steps of cortical visual processing (see pg. 47, abstract).
Furthermore, Li et al. demonstrate that infusion of CCK enabled neurons in the auditory cortex to start responding to a light stimulus that was paired with a noise burst or electrical stimulation of the auditory cortex (see pg. 319, right column, last paragraph). The literature reviewed by Li and coworkers also teaches that stimuli in one sensory modality can influence the activity of cortical areas associated with other sensory modalities (see pg. 321, right column, last paragraph); and that in humans auditory stimulus can activate the visual cortex after paired auditory-visual stimuli (see pg. 321, right column, last paragraph). For instance, silent lip-reading and light can activate the auditory cortex, and auditory stimuli can activate the visual cortex (see pg. 323, left column, first paragraph). Li et al.’s study using anesthetized rats, pairing a visual stimulus with a strong auditory stimulus for 20 trials in the presence of CCK enabled auditory cortical neurons to respond to the visual stimulus (see pg. 323, left column, first paragraph).Thus, Li et al.’s work demonstrates that in the presence of CCK, long-term plasticity in the auditory cortex was induced by pairing a visual stimulus with an auditory stimulus, thereby inducing plasticity within the auditory sensory modality as well as across visual and auditory sensory modalities (see pg. 325, left column, paragraph 2).
With respect to administrating a therapeutically effective amount of cholecystokinin receptor B (CCKBR) agonist to a subject in need thereof:
‘716 teaches a polypeptide and an application thereof as a CCK receptor agonist/antagonist (see ‘716, Abstract). According to ‘716, CCK plays an important role in the mechanism involving acetylcholine, y-aminobutyric acid, serotonin, opiates, growth hormone suppression, substance P and ion channels (see ‘716, pg. 1, second paragraph). Additionally, CCK receptor agonist can cause physiological and behavioral changes such as impact on learning knowledge; experiments have shown that CCK receptor agonists and antagonists can be used to treat diet, obesity, gallbladder cancer, pancreatic cancer, epilepsy, depression, and digestive disorders caused by excess gastric acid (see ‘716, pg. 1, third paragraph). In Example 1, ‘716 teaches using CCK8 as a positive control (see ‘716, top of pg. 11), with results showing that CCK8, as a positive control, was considered to have the strongest agonistic activity, and its high-concentration effect was the saturated state of cells (see ‘716, bottom of pg. 11). ‘716 also teaches that the polypeptide having a structure of Formula I may be included in a composition, especially a pharmaceutical composition, in an effective amount (see ‘716, pg. 8, paragraph 1). ‘716’s invention also relates to the use of the polypeptides of any structure shown in Formula I, II, III or IV as a CCK receptor agonist or antagonist, or in the preparation of a medicament for treating or preventing CCK receptor-related diseases (see ‘716, pg. 7, fourth paragraph). Additionally, ‘716’s Table 1 depicts compound HT-177 as having the sequence Ac-Trp-Nle-Asp-Phe(3-Br)-NH2 (see ‘716, Table 1 at pg. 52), which corresponds to the instantly claimed CCKBR agonist 3rl. As such, the teachings of ‘716 correspond to administering a therapeutically effective amount CCKBR agonist receptor (i.e., 3rl) to a subject in need thereof.
Moreover, ‘716 investigated whether compound HT-177 can induce long-term potentiation in the neocortex of memory-deficient mice (see pg. 85, Example 11, last paragraph). After stably recording excitatory postsynaptic field potentials for at least 15 minutes, compound HT-177 (i.e., 3rl agonist) was administered for five minutes to the brain slices cultured in vivo; and it was found that the basal field potential was significantly enhanced to 120-140% and the enhancement lasted for more than one hour (see ‘716, pg. 85, last paragraph, pg. 86, first paragraph and Fig. 10). Thus ‘716 shows that compound HT-177 could induce long-term potentiation in the neocortex of memory-deficient mice.
Before the effective filing date of the claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to combine the teachings of the cited prior art in order to arrive at the claimed method.
One of ordinary skill in the art would have been motivated to do so because it was known that:
-CCK receptor agonists, either general receptor agonist such as CCK8s or selective CCKB receptor agonist increase the excitability of layer 6 neocortical neurons by suppressing a leak K+ current; and because it has been hypothesized that corticothalamic input from layer 6 provide a modulatory input to first- and higher-order thalamic nuclei while higher order thalamic nuclei receive driver input from layer 5 corticothalamic neurons thus resulting in interconnection of different cortical areas, as taught by Chung et al.;
-layer six in the primary visual cortex of the mouse has a crucial role in controlling the gain of visually evoked activity in neurons of the upper layers without changing their tuning to orientation as taught by Olsen et al.;
-and because in the presence of CCK, long-term plasticity in the auditory cortex was induced by pairing a visual stimulus with an auditory stimulus, thereby inducing plasticity within the auditory sensory modality as well as across visual and auditory sensory modalities as taught by Li et al.
An ordinary skilled artisan would have had a reasonable expectation of success in achieving the claimed invention given that:
-layer 6 inputs have been referred to as modulatory in that these inputs may play an important role in setting the gain, or sensitivity, of neurons to afferent inputs, as taught by Chung et al.;
-layer 6 is the major mediator of cortical gain modulation and could be a node through which convergent inputs from several brain areas can regulate the earliest steps of cortical visual processing as taught by Olsen et al.;
- that stimuli in one sensory modality (e.g., an auditory stimulus) can influence the activity of cortical areas associated with other sensory modalities (e.g., a visual response) as discussed by Li et al;
-and given that cholecystokinin receptor agonist 3rl was shown to induce long-term potentiation in the neocortex of memory-deficient mice by enhancing and prolonging the basal field potential to 120-140% as demonstrated by ‘716.
Therefore combining the teachings of the cited prior art supports the claimed method for treating amblyopia by administering a therapeutically effective amount of cholecystokinin receptor B (CCKBR) agonist to a subject in need thereof by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention, pursuant to KSR.
Regarding claims 2 and 10, Chung et al. examined the actions of CCK8S and CCK4 across the concentration range 0.125-2.5µM (see pg. 12, left column, last paragraph).
‘716 teaches in Example 2, that the pharmacokinetic properties of HT-267, HT-177 (i.e., 3rl) and CCK4 (HT-9) in KM mice (male) were determined after intravenous administration (n = 4) (see ‘716, pg. 79, paragraph 2). Specifically, the above three polypeptides were dissolved in a solution of 5% DMSO and 95% secondary deionized water, respectively, and injected into the tail vein of KM mice at a dose of 1 mg/kg, respectively (see ‘716, pg. 79, paragraph 2). The results showed that the presence of CCK4 could not be detected in blood samples after tail vein injection, indicating that its concentration was lower than the detection limitation (50 ng/ml), possibly due to the rapid decomposition of CCK4 after intravenous injection (see ‘716, pg. 80, paragraph 1 and Table 2). Both compounds HT-267 and HT-177 showed a good half-life, 1.601 and 0.721 hours, respectively. At the same time, the time of Tmax was 0.033 and 0.25 hours, respectively (see ‘716, pg. 80, paragraph 1 and Table 2).
With respect to wherein the CCKBR agonist is administered at a dosage of from about 10 nM/kg to about 4.18 uM/kg; neither Chung et al. nor ‘716 identifies the dosage as nM/kg or µM/kg.
However, it is noted that ‘716 teaches determination of the pharmacokinetic properties of HT-267, HT-177 (i.e., 3rl) and CCK4 (HT-9) by injecting a dose of 1mg/kg to KM mice. The presence of CCK4 could not be detected in blood samples after tail vein injection, indicating that its concentration was lower than the detection limitation (50 ng/ml), and compounds HT-267 and HT-177 showed a good half-life, 1.601 and 0.721 hours, respectively. The dosage at which the CCKBR agonist is administered is clearly a result specific parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal CCKBR agonist dosage needed to achieve the desired result of a sufficient blood CCKBR agonist concentration. Thus, an ordinary skilled artisan would have been motivated to adjust the 1mg/kg of HT-177 (i.e., 3rl) and CCK4 (HT-9) dosage as taught by ‘716 to obtain various dosages including those as instantly claimed for treating amblyopia and/or regaining or improving visual acuity such that the dosage results in a sufficient blood HT-177 or CCK4 concentration, thereby resulting in a method for treating amblyopia and a method of regaining or improving visual acuity, because an ordinary skilled artisan would have been able to utilize the teachings of ‘716 to obtain various dosages parameters with a reasonable expectation of success. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of a dosage of CCKBR agonist would have been obvious at the time of applicant's invention. Therefore, the claimed invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, because the combined teachings of the prior art are fairly suggestive of the claimed invention. As such, the teachings of ‘716 suggest the claim limitations as recited in instant claims 2 and 10.
Regarding claims 3-5 and 11-13, as previously mentioned, ‘716 teaches that administration of CCKR agonists (i.e., the polypeptide having a structure of Formula I) to a subject may significantly improve the subject’s learning ability and memory deficiency and also prolong the effects of the improvements (see pg. 7, last paragraph). ‘716 also mentions that an effective amount usually means an amount sufficient to produce a therapeutically desired outcome, where the exact nature of the outcome varies according to the specific condition being treated (see ‘716, pg. 8, first paragraph).
Additionally, ‘716 teaches several embodiments where an intraperitoneal injection of CCK4 or 3rl is administered to memory deficient mice wherein the Morris water maze experiment was used to evaluate changes in memory (see ‘716, pp. 82-85, Examples 4-6, 8 and 11). In particular, Example 5 teaches that administration frequency and treatment duration differed according to the compound being administered (i.e., CCK4, HT-267), because the half-life of the compounds differed (see ‘716, pg. 82, Example 5). For instance, the half-life of CCK4 was too short (less than 5 minutes), intraperitoneal injection of the drug was given before each training, and the treatment was given four times a day, and the training was carried out four times a day, for a total of 10 days (see pg. 82, Example 5, second paragraph). HT-267 had a half-life of up to 1.601 hours, only one intraperitoneal injection was required per day, which can act on four trainings, so the treatment was given once a day, and the training was carried out four times a day, for a total of 8 days (see ‘716, pg. 82, last paragraph).
As such, the administration parameters recited in instant claims 3-5 and 11-13 are clearly a result specific parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal CCKBR agonist administration dose, frequence and duration of dose administration needed to achieve the desired result of treating amblyopia and/or regaining or improving visual acuity in a subject. Thus, an ordinary skilled artisan would have been motivated to adjust the frequency of administration as well as the duration of treatment as taught by ‘716 to determine the dose and frequency of administration as instantly claimed for treating amblyopia and/or regaining or improving visual acuity such that the dosage and frequency of administration results in a sufficient blood HT-177 or CCK4 concentration, thereby resulting in a method for treating amblyopia and a method of regaining or improving visual acuity. An ordinary skilled artisan would have been able to utilize the teachings of ‘716 to obtain various dosages and frequency of administration parameters with a reasonable expectation of success. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization dosage and frequency of administration of CCKBR agonists would have been obvious at the time of Applicant's invention. Therefore, the claimed invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, because the combined teachings of the prior art are fairly suggestive of the claimed invention. As such, the teachings of ‘716 suggest the claim limitations as recited in instant claims 3-5 and 11-13.
Regarding claims 7-8, and 16, ‘716 teaches that the subject may be a human, in particular the subject is a mammal, preferably a human (see ‘716, pg. 8, second paragraph). ‘716 also teaches that the effective amount of the polypeptide may depend on the species weight, age, and individual conditions of the subject (see ‘716, pg. 8, second paragraph). Therefore, ‘716’s teachings suggest that the subject is a human and the human could be an infant, a child, an adult and a combination thereof.
Regarding claim 15, Chung et al. teaches that CCK has been found to produce a variety of actions in different regions of the central nervous system including direct postsynaptic actions, increasing neurotransmitter release and modulating synaptic activity (see pg. 15, right column, second paragraph). However, Chung et el. do not expressly teach wherein the CCKBR agonists leads to opening of critical period of neuroplasticity in visual cortex.
Li et al. demonstrate that infusion of CCK enabled neurons in the auditory cortex to start responding to a light stimulus that was paired with a noise burst or electrical stimulation of the auditory cortex (see pg. 319, right column, last paragraph). As such, Li et al.’s work demonstrates neuroplasticity induced by local infusion of CCK into the auditory cortex of anesthetized thereby enabling visual responses of auditory neurons (see pg. 311, left column and pg. 313, Fig. 3).
Since it is known that neuroplasticity, also known as neural plasticity or brain plasticity, is a process that involves adaptive structural and functional changes to the brain in response to intrinsic or extrinsic stimuli by reorganizing its structure, functions, or connections as evidenced by Puderbaugh et al. (see pg. 1, Introduction).
Before the effective filing date of the claimed invention, an ordinary skilled artisan would have been motivated with reasonable expectation of success to arrive at the claimed method of regaining or improving visual acuity of a subject experiencing amblyopia and reduced visual acuity by administrating a therapeutically effective amount of CCKBR agonist to a subject. One of ordinary skill in the art would have been motivated to do so because it was known that in the presence of CCKBR agonists visual responses of auditory neurons were achieved, as taught by Li et al. One of ordinary skill in the art would have had a reasonable expectation of success, given that cholecystokinin increases neurotransmitter release and modulates synaptic activity as taught by Chung et al. Thus, combining the teachings of the prior art would support the instantly claimed method wherein the CCKBR agonist leads to opening of critical period of neuroplasticity in visual cortex by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention, pursuant to KSR.
In light of the foregoing discussion, the Examiner concludes that the subject matter defined by the above claims would have been obvious to one of ordinary skill in the art within the meaning of 35 USC 103. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references discussed above.
Response to Arguments
Applicant's arguments filed 06/17/2026 have been fully considered but they are not persuasive.
With respect to the 35 U.S.C. 112 rejections to claim 3; as being indefinite for failing to particularly point out and distinctly claim the subject matter (i.e., 112(b)); and as failing to comply with the written description requirement (new matter) (i.e., 112(a)). Applicants’ arguments have been fully considered but are not persuasive. The rejections have been maintained because the amendments did not cure the ambiguity with respect to the dose and the frequency of administration. Likewise, the newly added amendment is not supported by the instant specification, thereby the claim does not comply with the written description requirement, and still recites new matter.
With respect to the claim rejections under 35 U.S.C 103 to claims 1-5, 7-13 and 15-16; Applicants’ arguments have been fully considered but are not persuasive.
Applicants’ assert that the 35 U.S.C 103 to claims 1-5, 7-13 and 15-16 is an impermissible hindsight reconstruction, using the present application to select teachings in the cited art and combine the features therein to arrive at the claimed invention (see Remarks, filed 06/17/2026, pg. 6 of 9, second to last paragraph).
It is the Examiner’s understanding that Applicant is suggesting that the Examiner’s position fails to establish a prima facie case of obviousness because the prior art does not lead an artisan to the instant invention (see Remarks filed 06/17/2026, pg. 7 of 9, second paragraph). If Applicant means to suggest that the Examiner arrived at the instantly claimed invention via the use of improper hindsight, this is not persuasive because any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the Applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Here, Applicant fails to identify a single aspect of the claimed invention that was not taught, disclosed, or suggested by the prior art relied upon by the Examiner.
Applicants attest that none of the cited prior art suggest any link between CCK/CCKBR in somatosensory cortex and the treatment of amblyopia (see Remarks, filed 06/17/2026, pg. 6 of 9, bridging paragraph); these arguments have been considered but are not persuasive.
Applicants direct the reader to the teachings of Chung et al., who explicitly investigate layer 6b neurons in the somatosensory cortex; and who also demonstrate that layer 6 neocortical neurons when exposed to the general CCK receptor agonist CCK8S and the specific CCKB receptor agonist CCK4 at a concentration range of 0.125-2.5µM, exhibit an increase in excitability which ultimately translate to other circuits and/or neocortical areas that modulate the gain or sensitivity of neurons to afferent inputs (see discussion in 35 U.S.C 103 rejection above).
Per MPEP 2144(IV), the reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) ("One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings."); In re Lintner, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) (discussed below); In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991) (discussed below).
Thus, before the effective filing date of the claimed invention it was known that CCK8S is a general agonist for CCK receptors and CCK4 is a specific, selective agonist that targets CCKB receptors in layer 6 neocortical neurons; and that exposure of the CCK receptor and CCKB receptor to these agonist increases neuron excitability which ultimately translate to other circuits and/or neocortical areas that modulate the gain or sensitivity of neurons to afferent inputs. This is relevant because, in simple terms, amblyopia is a disorder of the visual cortex, wherein neural connections in the brain’s visual system shift toward supporting one eye, leaving the other eye (the amblyopic eye) less capable and functional. Therefore, administering CCK8 or CCK4 to a subject affected by amblyopia would likely result in circuits and/or neocortical areas, such as the visual cortex, that modulate the gain or sensitivity of neurons to afferent inputs, such as sound. Because before the effective filing date of the claimed invention, it was also known that stimuli in one sensory modality can influence the activity of cortical areas associated with other sensory modalities (see Li et al., pg. 321, right column, last paragraph); and that in humans auditory stimulus can activate the visual cortex after paired auditory-visual stimuli (see Li et al., pg. 321, right column, last paragraph). The combined teachings of Olsen et al., Puderbaugh et al., as well as the teachings of ‘716 provide evidence that help support the above motivation to combine the cited art (see 35 U.S.C 103 discussion above). Thus, contrary to Applicants’ arguments, it is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by Applicants.
Applicants argue that the rejection is based upon unrelated elements from different fields, namely somatosensory cortex (Chung), normal visual gain (Olsen), auditory cortex plasticity (Li), and general neuroplasticity (Puderbaugh); and that none of these references contain overlapping subject matter, shared functional purpose or an analogous technical field with one another (see Remarks, filed 06/17/2026, pg. 8 of 9, first paragraph). These arguments have been fully considered but are not persuasive.
Applicants’ statements amount to a suggestion that the Examiner’s position would be met with skepticism of experts (see Remarks, filed 06/17/2026, pg. 8 of 9, first paragraph). If Applicants mean to suggest the existence of skepticism of experts, such evidence should be filed per MPEP § 716.05 as evidence is required to establish skepticism of experts. In the absence of such evidence, such statements are understood to be unsupported conjecture of counsel. The prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)), including “all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments” (see, e.g., MPEP § 2123(I)), and no objective evidence rebutting this presumption has been placed on record to date.
The instantly claimed method is unpatentable over the cited prior art. Contrary to Applicants’ arguments, the overlapping subject matter among the cited references encompasses the brain, brain plasticity, neuronal connections, cholecystokinin receptor (CCK), and the effect of the agonists CCK8, CCK74. And as Applicants are aware, the brain is a complex organ with a complex network of neurons and neural pathways, wherein the visual cortex is also part of the neural network, and processes vision in stages and integrates it with other sensory, motor and cognitive systems. Therefore, it is not possible to isolate the effects of a CCKBR agonist to only the visual cortex, because the visual cortex is integrated with other brain areas.
In response to Applicants’ arguments that none of the references disclose any in vivo therapeutic efficacy of CCKBR agonist on visual disease pathology; nor predict that CCK8s, CCK4, or 3rl would reopen visual critical period plasticity or rescue amblyopic visual function (see Remarks, filed 06/17/2026, pg. 8 of 9, second paragraph). These arguments have been fully considered but are not persuasive.
It is the Examiner’s understanding that Applicants’ statements amount to a suggestion that the prior art is not fully enabled or operable. If Applicant is attempting to allege that the prior art is not enabling or inoperable Applicant is directed to MPEP § 2121(I), which notes that the prior art is presumed fully enabled for all that it discloses, and the burden is on the Applicant to rebut the presumption of operability (see, e.g., MPEP § 2121(I); MPEP § 716.07). No evidence of inoperability commensurate in scope with the requirements of MPEP § 716.07 have been placed on record at this time; critically, arguments of counsel cannot take the place of evidence in the record (see, e.g., In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965), and evidence is required to rebut the presumption of operability. Accordingly, the combined teachings of the cited prior art render the claimed invention obvious, because all the CCKBR agonist (i.e., CCK8s, CCK4 and compounds HT-1 to HT-292) taught by the prior art perform a recognized function.
Accordingly, the 35 U.S.C. 103 rejection to claims 1-5, 7-13 and 15-16 is herewith maintained.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/CLAUDIA ESPINOSA/ Patent Examiner, Art Unit 1654
/JULIE HA/ Primary Examiner, Art Unit 1654
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