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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06/02/25 has been entered.
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.
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 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.
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.
Response to Amendment
The Declaration of Chan, Lai Hang Leanne under 37 CFR 1.132 filed 07/18/2025 is insufficient to overcome the rejection of claims 1-5, 7-13 and 15-16 based upon the 35 U.S.C. 103 as set forth in the last Office action because:
Although Applicants work demonstrates that CCK plays a critical role in visual plasticity and suggest that targeting CCK neurotransmission via optogenetic stimulation of the dorsal lateral geniculate nucleus (dLGN) or pharmacological intervention with CCKBR agonist (3rl), represents a promising therapeutic avenue for amblyopia, Applicant’s findings do not preclude a finding of obviousness. It is noted that the features upon which applicant relies (i.e., the underlying mechanism by which CCKBR agonist (3r1) can restore visual plasticity in amblyopic mice) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The scope of instant claim 1 only encompasses treating amblyopia by administrating a therapeutically effective amount of CCKBR agonist to a subject in need thereof. Therefore, the scope of claim 1 and dependent claims do not correlate the underlying mechanism by which CCKBR agonist (3r1) can restore visual plasticity to administering a therapeutically effective amount of CCKBR agonist to a subject in need thereof.
Moreover, the fact that the inventor has recognized another advantage (i.e., the underlying mechanism by which CCKBR agonist (3r1) can restore visual plasticity in amblyopic mice), which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). Thus, even if the scope of the instant claim encompassed the underlying mechanism by which CCKBR agonist (3r1) can restore visual plasticity in amblyopic mice; and assuming arguendo that the cited art does not suggest CCKBR agonist as a treatment for amblyopia, since the prior art teaches that CCKBR agonist induce long-term potentiation in rat brains comparable to the natural CCKBR receptor agonist (CCK8); and since long-term potentiation is associated with synaptic plasticity/metaplasticity, it would naturally follow that a method for treating amblyopia by administrating a therapeutically effective amount of CCKBR agonist to a subject in need thereof would necessarily result in reduced visual acuity and/or improved visual acuity. As such, the reason (i.e., the underlying mechanism by which CCKBR agonist (3r1) can restore visual plasticity in amblyopic mice) an ordinary skilled artisan would modify the teachings of Castren and use CCKBR agonist (3r1) as part of a method of treating or alleviating the symptoms of amblyopia does not preclude a finding of obviousness. In other words, it is not necessary for the prior art to teach the underlying mechanism by which CCKBR agonist (3r1) can restore visual plasticity in amblyopic mice, and thus treatment amblyopia by administering an effective amount of CCKBR agonist.
Furthermore, pursuant to MPEP § 2144, a difference in objectives, if any, does not defeat the case for obviousness because 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. In re Linter, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) …; In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991) …” As such, the reason an ordinary skilled artisan would modify the teachings of Castren and use a CCKBR agonist as long-term synaptic potentiator in the method for treating amblyopia does not preclude a finding of obviousness. In other words, it is not necessary for the prior art to teach that the CKK receptor agonists therein can serve as SSRI, and thus CKK receptor agonists can be used for the treatment and prevention of CCK receptor-related diseases such as depression. As such, the evidence submitted for the purpose of traversing grounds of rejection is not dispositive for the obviousness rejection. In other words, the declaration refers to the cholecystokinin receptor B mechanism of action and its role in thalamocortical plasticity and not to the individual claims of the application. Thus, there is no showing that the objective evidence of nonobviousness is commensurate in scope with the claims. See MPEP §716.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Response to Arguments
1. Applicants' arguments, see Response, filed 06/02/2025, with respect to 35 U.S.C. 103 as being unpatentable over Castren et al. US Publication No. 2010/0093805 A1 published on April 15th, 2010 (herein after “Castren”); in view of the English version equivalent of CN113929737A published on January 14th, 2022 (WO2023/065716A1 English version equivalent published on April 27th, 2023 (herein after ‘716)), have been fully considered but they are not persuasive. The 35 U.S.C. 103 rejection to claims 1-5, 7-13 and 15-16 has been maintained.
New Rejections
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 doses delivered on alternate days for at least 4 doses.” However, the newly added limitation pertaining to the dose of CCKBR agonist administered, i.e., in doses delivered on alternate days for at least 4 doses, renders the claim indefinite because multiple interpretations of the limitation can be applied. For instance, an ordinary skilled artisan would not be able to ascertain whether the at least 4 doses are delivered in a range of 7 days, and a single dose is administered every other day (i.e., on days 1, 3, 5 and 7), for a total of at least 4 doses (first interpretation). Second interpretation: whether 4 individual doses are delivered on day one, 4 individual doses are delivered on day three, 4 individual doses are delivered on day five, and 4 individual doses are delivered on day 7, for a total of at least 4 doses on each alternate day. Third interpretation: one dose is delivered on the first day and 3 individual doses are delivered on the third day, for a total of at least 4 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 of the CCKBR agonist.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
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 “doses delivered on alternate days for at least 4 doses”, and the amendment gives room for multiple interpretations pertaining the administration of the CCKBR agonist, in particular to the number of doses delivered and the time range in which the doses are delivered. After carefully reviewing the evidence provided in the specification, it is noted that Example 1 at pp. 9, para[0050] provides evidence that supports the first interpretation (i.e., at least 4 doses are delivered in a range of 7 days, and a single dose is administered every other day (i.e., on days 1, 3, 5 and 7), for a total of at least 4 doses). However, the instant specification fails to provide evidence that support the second and third interpretations of the “doses delivered on alternate days for at least 4 doses”. Where the phrase is interpreted as: 4 individual doses are delivered on day one, 4 individual doses are delivered on day three, 4 individual doses are delivered on day five, and 4 individual doses are delivered on day 7, for a total of at least 4 doses on each alternate day; or as one dose is delivered on the first day and 3 individual doses are delivered on the third day, for a total of at least 4 doses, respectively. As such, the instantly claimed “doses delivered on alternate days for at least 4 doses”, has not been adequately supported.
Maintained/Modified Rejections in light of Amendments
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 1-2, 4-5, 7-13 and 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Castren et al. US Publication No. 2010/0093805 A1 published on April 15th, 2010 (herein after “Castren”); in view of the English version equivalent of CN113929737A published on January 14th, 2022 (WO2023/065716A1 English version equivalent published on April 27th, 2023 (herein after ‘716)); Leet et al. Curr Opin Ophthalmol. 2022 Nov 1;33(6):512-518 (herein after “Leet”); Maya Vetencourt et al., Science, 2008, vol. 320, pp. 385-388 (herein after “Maya Vetencourt”); Zhang et al., Medicinal Chemistry Research (2019) 28: 387-393 (herein after “Zhang”); and Li et al., Cell Research (2014), 24: 307-330 (herein after “Li”).
Regarding claim 1, a method for treating amblyopia by administrating a therapeutically effective amount of cholecystokinin receptor B (CCKBR) agonist to a subject in need thereof, wherein the CCKBR agonist is selected from the group consisting of CCK8s, CCK4, 3rl, and a combination thereof:
Castren teaches a method of treating or alleviating the symptoms of amblyopia (see Castren, Abstract), based on the discovery that repeated administration of a specific drug, which is known to be clinically active to treat depression in humans, results in improved vision of the amblyopic eye (see Castren, Abstract); thereby constituting a method for treating amblyopia as recited in instant claim 1. Amblyopia is a clinical condition which is characterized by a dysfunction in the processing of visual information (see Castren, pg. 1, para[0002]). Typically it is detected as reduced visual acuity in the absence of pathological findings in the ophthalmological examination (see Castren, pg. 1, para[0002]). The object of Castren’s invention is to provide a method of treating or alleviating amblyopia in humans who have passed the critical period of postnatal visual development (see Castren, pg. 2, para[0007]); thereby constituting treating a subject in need thereof as recited in instant claim 1.
Castren teaches that when adult rats are treated with fluoxetine for 4 weeks and subjected to MD (monocular deprivation) during the last week of the treatment, a dramatic shift in favor to the open eye is observed in the visual cortex (see Castren, pg. 3, para[0029]). This shift is qualitatively similar to that observed in young MD rats at the height of the critical period, since it was produced by a reduction of the response to stimulation of the deprived eye with no difference in the responsiveness to the stimulation of the open eye (see Castren, pg. 3, para[0029]). Treatment of adult rats with fluoxetine alone, without a deprivation of one eye, did not produce any changes in the responsiveness of either eye to visual stimulation, suggesting that the antidepressant drug treatment reinstates the critical period plasticity in the visual cortex, but a visual deprivation of one eye is required to produce a shift in binocularity in the visual cortex (see Castren, pg. 3, para[0029]). Furthermore, fluoxetine alone did not influence the orientation selectivity or cell responsiveness in the visual cortex (see Castren, pg. 3, para[0029]). As demonstrated in the Experimental part, if adult rats which have been subjected to MD early in development (postnatal day 21) are treated with fluoxetine perorally for 4 weeks with a dose which produces fluoxetine plasma levels similar to those seen in humans treated with fluoxetine for depression, and during the last two weeks of treatment are subjected to the reverse suture, there is a dramatic shift towards the eye which was closed during development but opened during the drug treatment (see Castren, pg. 4, para[0030]). Castren also teaches that antidepressant drugs increase the production of new neurons in the hippocampal dentate gyrus and increase axonal sprouting and synaptogenesis in hippocampus (see Castren, pg. 2, para[0006]). Evidence accumulated over the last decade suggests that antidepressant drugs are involved in the regulation of neuronal plasticity (see Castren, pg. 2, para[0006]). Castren’s invention is thus directed to the use of antidepressant drugs for the manufacture of a medicament for treating or alleviating amblyopia in humans who have passed the critical period of postnatal visual development (see Castren, pg. 2, para[0009]).
However, Castren does not expressly teach administrating a therapeutically effective amount of cholecystokinin receptor B (CCKBR) agonist; wherein the CCKBR agonist is selected from the group consisting of CCK8s, CCK4, 3rl and a combination thereof as recited in instant claim 1.
‘716 teaches a polypeptide and an application thereof as a CCK receptor agonist/antagonist (see ‘716, Abstract). According to ‘716, 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); thereby constituting administrating a therapeutically effective amount as recited in instant claim 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 (i.e., depression) (see ‘716, pg. 7, .fourth paragraph). Additionally, 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). It is noted that the sequence of compound HT-177 corresponds to the CCKBR agonist 3rl; thereby constituting wherein the CCKBR agonist is 3r1 as recited in instant claim 1.
Leet teaches that research has uncovered the mechanisms underlying ‘‘Hebbian’’ synaptic plasticity (i.e., during development, “neurons that fire together, wire together”) through the study of long-term potentiation (LTP), a phenomenon described initially in the hippocampus, but subsequently shown to be ubiquitous at excitatory synapses in the brain, including those in the primary visual cortex of primates, carnivores, and rodents (see Leet, pg. 513, left column, paragraph 1). Leet adds that, it was later revealed that synapses are bidirectionally modifiable and can also undergo long-term depression (LTD) when presynaptic activity consistently fails to strongly activate the postsynaptic neuron (see Leet, pg. 513, left column, paragraph 1). Leet also teaches that the BCM theory (named for the authors Bienenstock, Cooper, and Munro) postulates that synaptic strength is modified such that postsynaptic activity below a threshold will result in weakening of synaptic strength (LTD), while activity above this threshold results in long-term potentiation (LTP); and that the activity threshold itself can be modified based on previous neuronal activity (see Leet, pg. 514, Fig. 2 and its description). In the case of the BCM sliding threshold, the concept of metaplasticity serves synaptic network homeostasis (see Leet, pg. 514, left column, paragraph 1). The BCM assumption of a sliding threshold has been validated experimentally in visual cortex: a period of complete darkness will shift the LTP threshold in visual cortex to promote synaptic enhancement over depression (see Leet, pg. 514, left column, paragraph 1). Thus, visual experience induces metaplastic changes in the activity threshold that determines whether active synapses serving one eye or the other undergoes LTD or LTP (see Leet, pg. 514, left column, paragraph 1). Leet also discusses that emerging amblyopia treatment approaches abide by the framework of metaplasticity (i.e., synaptic plasticity varies depending on the history of cellular or synaptic activity) (see Leet, pg. 515, left column, paragraph 3). And that manipulation of the neuromodulatory systems is one of the emerging treatment categories and can be achieved exogenously via pharmacologic agents (see Leet, pg. 515, right column, second paragraph).
For instance, Maya-Vetencourt investigated whether fluoxetine, a widely prescribed medication for treatment of depression, restores neuronal plasticity in the adult visual system of the rat (see Maya-Vetencourt, pg. 385, Abstract). To assess the reduction of intracortical inhibition at the functional level, long-term potentiation (LTP) of layer II-III field potentials induced by θ-burst stimulation (TBS) of the white matter (WM-LTP) in the visual cortex, a form of synaptic plasticity that is absent in the adult because of the maturation of intracortical inhibitory circuitries (see Maya-Vetencourt, pg. 386, second column, paragraph 2). Maya Vetencourt found that WM-LTP was fully restored in fluoxetine-treated adult rats (see Maya-Vetencourt, pg. 386, second column, paragraph 2 and Fig. 2B).
Additionally, Zhang developed low-molecular weight CCKB receptor agonists capable of mediating long-term synaptic potentiation in vivo (see Zhang, pg. 388, left column, paragraph 2). Zhang demonstrated that compound 35 was observed to be the most potent CCKBR agonist with highest affinity and bioactivity (see Zhang, pg. 389, left column, last paragraph). Zhang teaches that no LTP (long-term potentiation) can be induced with HF (high frequency stimulation) in the CCK-/- mouse brain, but since CCK infusion into the CCK-/- mouse brain can induce a higher LTP in the neocortex when compared to normal mice, indicating overly expressed CCKB receptors in the neocortex; LTP induction in the CCK-/- mouse brain as the in vivo functional assay was used to examine the physiological effectiveness of compound 35 (see Zhang, pg. 391, left column, paragraph 2). Zhang’s results showed that compound 35 has a physiological effect, inducing long-term potentiation in rat brains comparable to the natural CCKB receptor agonist (see Zhang, pg. 392, left column, paragraph 1).
Li teaches that cholecystokinin from the entorhinal cortex enables neural plasticity in the auditory cortex (see Li, pg. 307, Title). Since CCK is the most abundant of all neuropeptides, and blocking CCK receptors suppresses conditioned fear, and knocking out the CCK-B receptor gene reduces anxiety-like behavior in rodents suggest that CCK is associated with memory function (see Li, pg. 308, left column, paragraph 2). This possibility is further supported by findings that CCK is involved in hippocampal long-term potentiation and long-term depression (see Li, pg. 308, left column, paragraph 2). Li demonstrates long-term plasticity in the auditory cortex was induced by pairing different stimuli in the presence of CCK, and the plasticity occurred within the auditory sensory modality as well as across visual and auditory sensory modalities (see Li, pg. 327, left column, paragraph 2). Li also teaches that in humans, an auditory stimulus can activate the visual cortex after paired auditory-visual stimuli (see Li, pg. 321, right column, last paragraph). For instance visual stimuli, such as silent lip-reading and light, can activate the auditory cortex and auditory stimuli can activate the visual cortex (see Li, pg. 323, left column, first paragraph). Li demonstrated that using anaesthetized 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 Li, pg. 323, left column, paragraph 1). Li concluded that the medial temporal lobe enables cortical plasticity through the release of CCK from neurons in the perirhinal and entorhinal cortices (see Li, pg. 325, left column, paragraph 2).
As such, the teachings of Leet, suggest that neuromodulatory systems can be manipulated exogenously via pharmacologic agents which modifying the activity threshold based on previous neuronal activity and results in long-term potentiation (LTP), more specifically in LTP in the visual cortex. Since the teachings of Maya Vetencourt, Zhang and Li, suggest that fluoxetine and a CCKBR agonist, induce metaplastic changes in the activity threshold thereby resulting in restoration of neuronal plasticity via long-term potentiation (LTP); an ordinary skilled artisan would have been motivated to combine the teachings of Castren and ‘176, with the above teachings of Leet, Maya Vetencourt, Zhang and Li in order to arrive at the claimed method. From the teachings of the references, the Examiner recognizes that it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of treating or alleviating the symptoms of amblyopia, by substituting Castren’s antidepressant drug treatment (i.e., fluoxetine) with compound HT-177 (i.e., CCKBR agonist 3rl) of ‘716, thereby resulting in a method for amblyopia by administrating a therapeutically effective amount of cholecystokinin receptor B (CCKBR) agonist to a subject in need thereof, wherein the CCKBR agonist is selected from the group consisting of CCK8s, CCK4, 3rl, and a combination thereof.
One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so because it was known that antidepressant drugs are involved in the regulation of neuronal plasticity as taught by Castren; because it was known that long-term potentiation (LTP) was ubiquitous at excitatory synapses in the primary visual cortex of primates, carnivores, and rodents; synaptic strength can be modified such that postsynaptic activity above a threshold results in long-term potentiation (LTP), because the activity threshold itself can be modified based on previous neuronal activity; and exogenous manipulation of the neuromodulatory systems via pharmacologic agents (e.g., fluoxetine) is one of the emerging amblyopia treatment categories as taught by Leet; and because it was also known that fluoxetine, a widely prescribed medication for the treatment of depression restores neuronal plasticity in the adult visual system of the rat as taught by Maya Vetencourt. Furthermore, one of ordinary skill in the art would have been motivated to do so because CCK infusion into the CCK-/- mouse brain was known to induce a higher LTP in the neocortex when compared to normal mice, indicating overly expressed CCKB receptors in the neocortex as taught by Zhang; and because it was known pairing a stimuli (visual) in the presence of CCK induces long-term plasticity in the auditory cortex as taught by Li.
One of ordinary skill in the art would have had been motivated with reasonable expectation of success given that that fluoxetine (i.e., antidepressant drug treatment) was known to reinstate the critical period plasticity in the visual cortex; given that the white matter (WM-LTP) in the visual cortex, a form of synaptic plasticity that is absent in the adult because of the maturation of intracortical inhibitory circuitries was fully restored in fluoxetine-treated adult rats; given that a low molecular weight CCKB receptor agonists was known to be capable of mediating long-term synaptic potentiation in vivo; and given that the medial temporal lobe enables cortical plasticity through the release of CCK from neurons in the perirhinal and entorhinal cortices. Therefore, substituting CCK8 or 3r1 as a cholecystokinin polypeptide agonist of ‘716 instead of the anti-depressant fluoxetine would support the method of treating or alleviating the symptoms of amblyopia by regaining or improving visual acuity 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 and/or the simple substitution of one known element for another to obtain predictable results pursuant to KSR.
Regarding claims 2 and 10, wherein the CCKBR agonist is administrated at a dosage of from about 10 nM/kg to about 4.18 uM/kg:
Castren teaches that adult rats at the postnatal day (P) 70 were systemically treated with fluoxetine (0.2 mg ml-1 drinking water) (Fluoxetine-hydrochloride, Galena, Prato-Italy) during 4 weeks (see Castren, pg. 5, para[0041]). This method of administration yields steady-state plasma concentrations of 356±99 ng/ml in rats, which is within the recommended plasma concentration for the treatment of depression in humans (50-450 ng/ml) (see Castren, pg. 5, para[0041]). Therefore, the dose of the antidepressant drug administered is expected to be at least at the level of that recommended for the treatment of depression (see Castren, pg. 4, para[0036]).
‘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 ‘715, 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 ‘715, pg. 80, paragraph 1 and Table 2). However, neither reference identifies the dosage as nM or µM/kg.
With respect to wherein the CCKBR agonist is administered at a dosage of from about 10 nM/kg to about 4.18 uM/kg, 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 or preventing amblyopia and 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 or preventing 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 4 and 12, with respect to wherein the subject is treated for a period of about 4 weeks to about 6 months:
Castren also teaches that if adult rats which have been subjected to MD early in development (postnatal day 21) are treated with fluoxetine perorally for 4 weeks with a dose which produces fluoxetine plasma levels similar to those seen in humans treated with fluoxetine for depression, and during the last two weeks of treatment are subjected to the reverse suture, there is a dramatic shift towards the eye which was closed during development but opened during the drug treatment (see Castren, pg. 4, para[0030]), thereby constituting where the subject is treated for a period of about 4 weeks as recited in instant claims 4 and 12. Additionally, because clinically relevant effect of antidepressant drugs in depressed human patients occurs with a delay of several weeks, preferably, the antidepressant drug is also in the case of amblyopia administered repeatedly for a period of several weeks before the commencement of the occlusion therapy (see Castren, pg. 4, para[0035]). The total duration of the drug treatment will depend on the clinical response achieved, but it is to be expected that changes will not take place as rapidly as was observed in rats in the Experimental part (within one week), but that a treatment or the combination of treatment and rehabilitation will need to be administered for a longer period of time, for example, a year (see Castren, pg. 4, para[0035]), thereby constituting wherein the subject is treated for a period of about 6 months as recited in instant claims 4 and 12.
Additionally and/or alternatively, MPEP 2144.05(I) states that "[i]n the case where the claimed ranges "overlap or lie inside ranges discloses by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%". The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.) Moreover, the Federal Circuit found that a prima facie case existed where a claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms and the prior art taught that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." In re Geisler, 116 F.3d 1465, 1469-82, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997). Therefore, the claimed method wherein the subject is treated for a period of about 4 weeks to about 6 months would have been obvious to one of ordinary skill in the art since the prior art range (i.e., 4 weeks up to several weeks or up to a year) lies within the claimed treatment period (i.e., of about 4 weeks to about 6 months). Therefore, the teachings of Castren are suggestive of the claim limitations as recited in instant claims 4 and 12.
Regarding claims 5 and 13, wherein the CCKBR agonist is administrated via intraperitoneal administration:
Castren teaches a method of treating or alleviating the symptoms of amblyopia by repeated administration of a specific drug, which is known to treat depression in humans. However, Castren does not expressly teach where the anti-depressant drug is administered intraperitoneally.
‘716 teaches that memory-deficient mice were randomized into six groups, with the first group given intraperitoneal injection of the CCK4 solution, the second group given intraperitoneal injection of the solvent of CCK4 solution as a control, the third group given intraperitoneal injection of the compound HT-267 solution, the fourth group given intraperitoneal injection of the compound HT-177 solution, the fifth group given intraperitoneal injection of the compound HT-178 solution, and the sixth group given intraperitoneal injection of the solvent of compound solution as a control (see ‘716, pg. 83, paragraph 3). The term injection includes intraperitoneal, intravenous, intramuscular, subcutaneous, and intradermal administration (see ‘716, pg. 8, fourth paragraph), thereby suggesting wherein the CCKBR agonist is administrated via intraperitoneal administration as recited in instant claims 5 and 13.
Regarding claims 7 and 16, with respect to wherein the subject is human:
Castren teaches that the term “human having passed the critical period of postnatal visual development” is intended to mean all human beings (adolescents, adults) having passed the critical period of postnatal visual development (see Castren, pg. 2, para[0008]). Additionally, it is known that occlusion treatments are not effective in humans after the age of about 10 years (see Castren, pg. 4, para[0034]). There are no reports of enhanced vision of the amblyopic eye in human having passed the critical period of postnatal visual development taking antidepressants for mood disorders, which is not surprising, since occlusion treatments are required for the prevention or amblyopia in the childhood (see Castren, pg. 4, para[0034]). The closure of the critical period is gradual but typically in humans the critical period does not extend beyond the age of about 10 years (see Castren, pg. 2, para[0008]). Therefore, the teachings of Castren satisfy the claim limitation with respect to where the subject is human as recited in instant claim 7 and 16.
Regarding claim 8, wherein the subject is selected from the group consisting of an infant, a child, an adult, and a combination thereof:
Castren teaches that occlusion therapy only works during a critical period of postnatal development; after the gradual closure of the critical period in adolescence, in humans typically by the age of 10 years, occlusion no longer helps and amblyopia remains permanent (see Castren, pg. 1, para[0002]), thereby constituting wherein the subject is selected from the group consisting of an infant, a child, an adult and a combination thereof as recited in instant claim 8.
Regarding claim 9, a method of regaining or improving visual acuity of a subject experiencing amblyopia and or reduced visual acuity by administrating a therapeutically effective amount of CCKBR agonist to the subject, wherein the CCKBR agonist is selected from the group consisting of CCK8s, CCK4, 3rl, and a combination thereof:
As discussed above for claim 1, Castren teaches a method of treating or alleviating the symptoms of amblyopia by repeated administration of a specific drug (i.e., fluoxetine), which is known to be clinically active to treat depression in humans, thereby resulting in in improved vision of the amblyopic eye (see Castren, Abstract). Castren adds that in rats, monkeys and humans, it is well established that closure of a single eye (monocular deprivation, MD) for a relatively short period (for example, a week) during the critical developmental period produces a drastic rearrangement in the innervation and function of the visual cortex such that the open eye becomes dominant at the expense of the closed eye (see Castren, pg. 3, para[0029]). This rearrangement is reflected as a dramatic reduction in the visual acuity of the closed eye, and can be observed in rats by using electrophysiological or behavioral measures (see Experimental part) (see Castren, pg. 3, para[0020]). As described in the Experimental part, when adult rats are treated with fluoxetine for 4 weeks and subjected to MD (monocular deprivation) during the last week of the treatment, a dramatic shift in favor to the open eye is observed in the visual cortex (see Castren, pg. 3, para[0029]). This shift is qualitatively similar to that observed in young MD rats at the height of the critical period, since it was produced by a reduction of the response to stimulation of the deprived eye with no difference in the responsiveness to the stimulation of the open eye (see Castren, pg. 3, para[0029]). Treatment of adult rats with fluoxetine alone, without a deprivation of one eye, did not produce any changes in the responsiveness of either eye to visual stimulation, suggesting that the antidepressant drug treatment reinstates the critical period plasticity in the visual cortex, but a visual deprivation of one eye is required to produce a shift in binocularity in the visual cortex (see Castren, pg. 3, para[0029]). Furthermore, fluoxetine alone did not influence the orientation selectivity or cell responsiveness in the visual cortex (see Castren, pg. 3, para[0029]). As demonstrated in the Experimental part, if adult rats which have been subjected to MD early in development (postnatal day 21) are treated with fluoxetine perorally for 4 weeks with a dose which produces fluoxetine plasma levels similar to those seen in humans treated with fluoxetine for depression, and during the last two weeks of treatment are subjected to the reverse suture, there is a dramatic shift towards the eye which was closed during development but opened during the drug treatment (see Castren, pg. 4, para[0030]). More importantly, the visual acuity of the opened eye is regained and binocularity is restored (see Castren, pg. 4, para[0030]), thereby constituting a method of regaining or improving visual acuity as recited in instant claim 9. These observations suggest that the antidepressant fluoxetine induces a reopening of the developmental critical period in adult mammals and enables functional reorganization within the visual cortex comparable to those occurring at the height of the critical period (see Castren, pg. 4, para[0030]).
Regarding claim 11, wherein the CCKBR agonist is administrated at a frequency of about 4 times a week:
Castren teaches that to assess ocular dominance plasticity, one week of monocular deprivation (MD) was performed through eyelid suturing at the beginning of the third week of repeated fluoxetine (P90) or vehicle administration (see Castren, pg. 5, para[0042]). At the end of repeated fluoxetine administration adult animals (P100), monocularly deprived for one week, were anesthetized with urethane (see Castren, pg. 5, para[0044]). Castren also teaches that because clinically relevant effect of antidepressant drugs in depressed human patients occurs with a delay of several weeks, preferably, the antidepressant drug is also in the case of amblyopia administered repeatedly for a period of several weeks before the commencement of the occlusion therapy (see Castren, pg. 4, para[0035]). It may also be possible to combine a continuous drug treatment with a periodic occlusion therapy, or both drug treatment and occlusion may be given for a shorter period and then repeated later for a number of times until a desirable response is obtained (see Castren, pg. 4, para[0035]). As discussed in the claim interpretation section above, “about” encompasses a frequency of administrating the CCKBR agonist ranging from four times a week or 1 dose a week or daily up to seven times a week or every other day, thereby the teachings of Castren are suggestive of the CCKBR agonist being administrated at a frequency of about 4 times a week as recited in instant claim 11.
With respect to wherein the CCKBR agonist is administrated at a frequency of about 4 times a week, it is noted that Castren et al. teach repeatedly fluoxetine administration to adult animals for a period of several weeks. The frequency of administering the anti-depressant drug 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 frequency of administration needed to achieve the desired results. Thus, an ordinary skilled artisan would have been motivated to modify the frequency of administration of the antidepressant as taught by Castren et al., for treating or preventing amblyopia and for regaining or improving visual acuity, because an ordinary skilled artisan would have been able to utilize the teachings of Castren et al. to obtain various CCKBR agonist administration frequencies parameters with a reasonable expectation of success. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of the CCKBR agonist administration frequency 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.
Regarding claim 15, wherein the CCKBR agonist leads to opening of critical period of neuroplasticity in visual cortex:
Castren teaches that GABA-mediated cortical inhibition increases and matures during the postnatal development (see Castren, pg. 4, para[0033]). It has been demonstrated that this increase in cortical inhibition critically contributes to the closure of the critical period (see Castren, pg. 4, para[0033]). Cortical GABA content increases towards the end of the critical period and if this increase in GABA is prevented, the critical period remains open (see Castren, pg. 4, para[0033]). Conversely, as demonstrated in the Experimental part, 3 week peroral administration of fluoxetine leads to the reduction of cortical extracellular GABA levels which leads to the reactivation of the critical period plasticity in the visual cortex (see Castren, pg. 4, para[0033]). If cortical GABA signaling is artificially increased by intracortical infusion of GABA-A receptor enhancer diazepam during the peroral administration of fluoxetine, enhanced plasticity in the adult visual cortex is prevented (see Castren, pg. 4, para[0033]). These observations suggest that the antidepressant fluoxetine induces a reopening of the developmental critical period in adult mammals and enables functional reorganization within the visual cortex comparable to those occurring at the height of the critical period (see Castren, pg. 4, para[0030]), thereby constituting wherein the CCKBR agonist leads to opening of critical period of neuroplasticity in visual cortex as recited in instant claim 15.
Accordingly, the teachings of Castren, when combined with the teachings of ‘716, Leet, Maya Vetencourt and Zhang are suggestive of the claim limitations as recited in instant claims 1-2, 4-5, 7-13 and 15-16.
Response to Arguments
Regarding Applicants’ arguments, with respect to the 35 U.S.C 103 rejection to claims 1-5, 7-13 and 15-16, have been considered but are not persuasive.
As discussed in the rejection above, the combined teachings of Castren and ‘716 suggest a method for treating amblyopia by administrating a therapeutically effective amount of cholecystokinin receptor B (CCKBR) agonist to a subject in need thereof, wherein the CCKBR agonist is selected from the group consisting of CCK8s, CCK4, 3rl, and a combination thereof. Thus, the updated 35 U.S.C 103 rejection above renders the amended claims obvious.
In response to Applicants’ arguments that without first reading the present application, the skilled person in the art could not be readily able to have the requisite expectation of success in replacing fluoxetine in Castren with a CCKBR agonist (see Response, filed 06/02/2025, pg. 6, paragraph 2), and that without specific guidance from prior art, those skilled in the art could not readily come up with selecting CCK8s, CCK4 and 3r1 out of so many compounds and then further combine with Castren in order to arrive at the claimed invention (see Response, filed 06/02/2025, pg. 6, paragraph 3), are found unpersuasive.
It must be recognized that 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). See MPEP 2142 (X)(A). Furthermore, obviousness does not require absolute predictability, however, at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness. In re Rinehart, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976). See MPEP 2143.02(II).
The combination of references (i.e., Castren and ‘716) does not represent impermissible hindsight because it was well known that the antidepressant fluoxetine reinstates the critical period plasticity in the visual cortex as taught by Castren. Therefore, an ordinary skilled artisan would have been motivated with reasonable expectation of success to substitute the pharmacological agent (i.e., fluoxetine) for a CCKB receptor agonist capable of inducing long-term potentiation/plasticity in the visual cortex such as any of the CCK8s, CCK4, 3r1 or a combination thereof. An ordinary skilled artisan would have been motivated to make the substitution because it was also known that manipulation of the neuromodulatory systems via pharmacologic agents such as fluoxetine is one of the emerging amblyopia treatment categories; because it was also known that CCK is involved in hippocampal long-term potentiation, and that by pairing a stimuli (i.e., visual or auditory) in the presence of CCK induces plasticity within the auditory sensory modality as well as across visual and auditory sensory modalities. Therefore, CCKBR agonist, just as fluoxetine (i.e., a widely prescribed medication for the treatment of depression) are capable of restoring neuronal plasticity in the adult visual system by potentiating the responses of cortical neurons. Thus, substituting a pharmacologically agent that reinstates the critical period plasticity in the visual cortex for a CCKB receptor agonist that can induce long term potentiation in the neocortex would have been obvious to an ordinary skilled artisan before the effective filing date of the claimed invention.
In response to Applicants’ arguments that there is no experimental data in ‘716 showing that the CCK receptor agonists therein can serve as SSRI (Selective Serotonin Reuptake Inhibitor) and that the ‘716 generally mentions that the CCK receptor agonist/antagonist can be used for the treatment and prevention of CCK receptor-related diseases such as depression (see Remarks, filed 06/02/2025, pg. 6, second to last paragraph), it is found unpersuasive.
It is noted that the features upon which applicant relies (i.e., mechanism of action by which CKKBR agonist/antagonist treat amblyopia) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The scope of instant claim 1, does not encompass a mechanism of action or pathway by which CCKBR agonist treats amblyopia. Rather, the scope of instant claim 1 only encompasses treating amblyopia by administrating a therapeutically effective amount of CCKBR agonist to a subject in need thereof. Therefore, the scope of claim 1 and the dependent claims do not correlate to a mechanism of action or pathway or therapeutic strategy for the treatment of amblyopia. Additionally, as discussed above in the “Response to Amendments” section, the fact that the inventor has recognized another advantage (i.e., the underlying mechanism of CCKBR agonist in the treatment of amblyopia) and a difference in objectives, if any, between the prior art and the instantly claimed invention does not defeat the case for obviousness. Please refer to “Response to Amendments” above.
In response to Applicants’ arguments that he present application has proved that post-critical period administration of the CCKBR agonist (3rl) can restore lost visual acuity in amblyopic animals, which is neither disclosed nor suggested in prior art references (see Remarks, filed 06/02/2025, pg. 7, paragraph 2); it is found unpersuasive.
As discussed in the action mailed on 12/02/2024, it is acknowledged that there is not a single reference that teaches and/or suggests every claim limitation recited in instant claim 1 and the dependent claims. However, Applicants are respectfully reminded that the rejections supra are based on obviousness. Pursuant to MPEP 2142, 35 USC 103 authorizes a rejection where, to meet the claim, it is necessary to modify a single reference or to combine it with one or more other references (emphasis added). The Examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, as discussed above in the 35 U.S.C 103 rejection above, the teachings of Castren, ‘716, Leet, Maya Vetencourt, Zhang, and Li are suggestive of the claim limitations as recited in instant claims 1-2, 4-5, 7-13 and 15-16. Castren’s invention is directed to the use of antidepressant drugs for the manufacture of a medicament for treating or alleviating amblyopia in humans who have passed the critical period of postnatal visual development (see Castren, pg. 2, para[0009]). ‘716 teaches a polypeptide and an application thereof as a CCK receptor agonist/antagonist such as CCK8 and 3r1, which 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). Leet teaches that excitatory synapses in the brain, including those in the primary visual cortex are bidirectional and modifiable and can undergo long-term depression (LTD), i.e., when presynaptic activity consistently fails to strongly activate the postsynaptic neuron, or long-term potentiation (LTP), i.e., persistent strengthening of synapses bases on recent patterns of activity; and that manipulation of the neuromodulatory systems is one of the amblyopia emerging treatment categories and can be achieved exogenously via pharmacologic agents. Maya Vetencourt teaches that fluoxetine restores neuronal plasticity in the adult visual system of the rat by restoring white matter long-term potentiation in the visual cortex, a form of synaptic plasticity that is absent in the adult because of the maturation of intracortical inhibitory circuitries. Zhang teaches that a CCKB receptor agonists is capable of mediating long-term synaptic potentiation in vivo; and Li teaches that long-term plasticity in the auditory cortex was induced by pairing different stimuli in the presence of CCK, and the plasticity occurred within the auditory sensory modality as well as across visual and auditory sensory modalities. As such, the question is (1) whether a person of ordinary skill in the art would be motivated and expected to treat amblyopia by administering a polypeptide such as CCK8 or 3r1, which is capable of mediating long-term synaptic potentiation and is used as an anti-depressant, and (2) whether a person of ordinary skill in the art would be motivated and expected to treat amblyopia by administering a medicament manufactured with an antidepressant drug. The Examiner maintains that the answers to these questions are yes in light of the teachings of ‘716, Leet, Zhang and Li for question one and Castren and Maya Vetencourt for question two. Thus, without evidence to the contrary, the Examiner maintains that an ordinary skilled artisan would be motivated with a reasonable expectation of success to substitute Fluoxetine in Castren with the CCKBR agonist of ‘716 to restore the visual plasticity in amblyopia.
Accordingly, the 35 U.S.C 103 rejection is maintained as Applicants’ arguments are found unpersuasive.
Conclusion
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/CLAUDIA ESPINOSA/Patent Examiner, Art Unit 1654
/THEA D' AMBROSIO/Primary Examiner, Art Unit 1654
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