Patent Application 17802183 - COMPOSITION FOR USE IN PREVENTION OR TREATMENT - Rejection

Patent Application 17802183 - COMPOSITION FOR USE IN PREVENTION OR TREATMENT

Title: COMPOSITION FOR USE IN PREVENTION OR TREATMENT OF OESOPHAGEAL DISEASES LINKED TO EPITHELIAL BARRIER DEFECTS

Application Information

• Invention Title: COMPOSITION FOR USE IN PREVENTION OR TREATMENT OF OESOPHAGEAL DISEASES LINKED TO EPITHELIAL BARRIER DEFECTS
• Application Number: 17802183
• Submission Date: 2025-05-15T00:00:00.000Z
• Effective Filing Date: 2022-08-25T00:00:00.000Z
• Filing Date: 2022-08-25T00:00:00.000Z
• National Class: 514
• National Sub-Class: 456000
• Examiner Employee Number: 76066
• Art Unit: 1625
• Tech Center: 1600

Rejection Summary

• 102 Rejections: 1
• 103 Rejections: 1

Cited Patents

No patents were cited in this rejection.

Office Action Text

    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 .

 Non-Final Rejection 

 The Status of Claims:
Claims 1-20 are pending. 
Claims 1-20 are rejected. 

DETAILED ACTION
1. 	Claims 1-20 are under consideration in this Office Action.
 					       Priority 
2.	It is noted that this application is a 371 of PCT/EP2021/052808 02/05/2021 , which has a foreign priority document, NETHERLANDS NL2025009 02/27/2020.
.

    Drawings
3.         The drawings filed on 8/25/22 are accepted by the examiner. 
        IDS
4.          The IDS filed on 8/25/22 & 4/30/25 are reviewed by the examiner.



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.


Claims 1-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA  the applicant regards as the invention.
The term "quercetin and myricetin is comprised in the composition in an amount of 0.001-100 mg" used in claim 1 is not clear, since it does not clearly indicate whether the 0.01-100 mg range refes to the sum of the amounts of quercirin and myrecitn or the individual amounts of querecitin and myricitin.

Claim 13 provides for the composition for use , but, since the claim does not set forth any steps involved in the method/process, it is unclear what method/process
applicant is intending to encompass. A claim is indefinite where it merely recites a use without any active, positive steps delimiting how this use is actually practiced.
Claim 13 is rejected under 35 U.S.C. 101 because the claimed recitation of
a use, without setting forth any steps involved in the process, results in an
improper definition of a process, i.e., results in a claim which is not a proper
process claim under 35 U.S.C. 101. See for example Ex parte Dunki, 153 USPQ
678 (Bd.App. 1967) and Clinical Products, Ltd. v. Brenner, 255 F. Supp. 131, 149
USPO 475 (D.D.C. 1966).
Rev. 1, December 1997 7-24


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.

 	Claims 1-20 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for treating specific gastroesophageal reflux disease or Eosinophilic Esophagitis, does not reasonably provide enablement for preventing the diseases. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. Applicants are not enabled for preventing any of these diseases. The only established prophylactics are vaccines not the quercetin (2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxychromen-4-one) and/or myricetin (3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)-4H-1-benzopyran-4-one) and/or myricetin (3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)-4H-1-benzopyran-4-one) such as present here. In addition, it is presumed that “prevention” of the claimed diseases would require a method of identifying those individuals who will develop the claimed diseases before they exhibit symptoms. There is no evidence of record that would guide the skilled clinician to identify those who have the potential of becoming afflicted. 
“The factors to be considered [in making an enablement rejection] have been summarized as the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art, and the breadth of the claims”, In re Rainer, 146 USPQ 218 (1965); In re Colianni, 195 USPQ 150, Ex parte Formal, 230 USPQ 546. 1) As discussed above, preventing diseases requires identifying those patients who will acquire the disease before gastroesophageal reflux disease or Eosinophilic Esophagitis occurs. This would require extensive and potentially opened ended clinical research on healthy subjects. 2) 
The passage spanning  from paragraphs#19-20 on page 3 to a  paragraph#24 line on page 4 mentions the diseases such as heartburn and GERD Applicant intend to treat. 3) There is no working example of such a preventive procedure in man or animal in the specification. 4) The claims rejected are drawn to clinical *** medicine and are therefore physiological in nature. 5) The state of the art is that no general procedure is art-recognized for determining which patients generally will become gastroesophageal reflux disease or Eosinophilic Esophagitis before the fact. 6) The artisan using Applicants invention would be a Board Certified physician in gastroesophageal reflux disease or Eosinophilic Esophagitis diseases with an MD degree and several years of experience. Despite intensive efforts, pharmaceutical science has been unable to find a way of getting a compound to be effective for the prevention of gastroesophageal reflux disease or Eosinophilic Esophagitis generally. Under such circumstances, it is proper for the PTO to require evidence that such an unprecedented feat has actually been accomplished, In re Ferens, 163 USPQ 609. No such evidence has been presented in this case. The failure of skilled scientists to achieve a goal is substantial evidence that achieving such a goal is beyond the skill of practitioners in that art, Genentech vs. Novo Nordisk, 42 USPQ2nd 1001, 1006. This establishes that it is not reasonable to any agent to be able to prevent gastroesophageal reflux disease or Eosinophilic Esophagitis generally. That is, the skill is so low that no compound effective generally against gastroesophageal reflux disease or Eosinophilic Esophagitis has ever been found let alone one that can prevent such conditions. 7) It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved", and physiological activity is generally 
considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). 8) The claims broadly read on all patients, not just those undergoing therapy for the claimed diseases. 
The Examiner suggests deletion of the word “preventing” from the claims.


Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –

(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.


Claim(s) 1, 3 and 12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated clearly by Rao et al (EUROPEAN JOURNAL OF PHARMACOLOGY, ELSEVIER SCIENCE, NL, vol. 589, no. 1-3, 28 July 2008 (2008-07-28), pages 233-238).


Rao et al  descries on the protective effects of quercetin and alpha-tocopherol individually on experimental reflux oesophagitis in rats, thereby proposing inherently a method of treating gastroesophageal reflux disease . Quercetin is administred orally at a dose of 1OOmg/kg to rats of 140-160 g. The beneficial effects of quercetin and alpha-tocopherol on oesophageal mucosal damage are attributed to their antioxidant properties. The document discloses that the results of the study suggest that antioxidants could attenuate the severity of reflux oesophagitis and prevent the oesophageal mucosal damage and validate their therapeutic use in GERO. (see abstract ; page 234, a section of 2.1) These are identical with the claims inherently.



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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.

5.	Claims 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Rao et al (EUROPEAN JOURNAL OF PHARMACOLOGY, ELSEVIER SCIENCE, NL, vol. 589, no. 1-3, 28 July 2008 (2008-07-28), pages 233-238) in view of Legge et al  (WO 2019/153046 A1) and Wikipedia (Alginic acid, December, 2018, p. 1-5).

Applicant claims the followings:
1. A method for prevention or treatment of gastroesophageal reflux disease wherein the quercetin and/or myricetin is comprised in the composition in an amount of 0.01 - 100 mg, and wherein the composition does not comprise a hydrolyzed protein source comprising whey and casein; a lipid; at least one pre-gelatinized starch; a low-methylated pectin; and/or at least one additional carbohydrate.  
2. (Currently Amended) A method for prevention or treatment of Eosinophilic Esophagitis in a patient in need thereofComposition comprising administeringtotlheatientacomposition comprising quercetin (2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxychromen-4-one) and/or myricetin (3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)-4H-1-benzopyran-4-one) ¾\#e> 
3. (Currently Amended) The methodComposition for use according to anyone of the previous claimsclaimj, wherein the ±fx:re&ovit¾smar4i>reinforcsfinioesophagus wall barrier function in the patient.  
4. (Currently Amended) The methodComposition for use according to anyone of the previous claimsclaimJ, wherein the patientuse is ma pregnant woman or i--a paediatric patient.  
5. (Currently Amended) The methodComposition for use according to anyone of the previous claimsclaimj,the composition comprising quercetin (2-(3,4-dihydroxyphenyl)-3,5,7- trihydroxychromen-4-one) and myricetin (3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)-4H-1- benzopyran-4-one).  
6. (Currently Amended) The methodComposition for use according to anyone of theprevious claimsclaimV_, wherein the composition comprises genistein (5,7-dihydro-3-(4- hydroxyphenyl)chromen-4-one) and/or berberine (5,6-dihydro-9,10-dimethoxybenzo[g]-1,3- benzodioxolo[5,6-a] quinolizinium).  
7. (Currently Amended) The methodComposition for use according to anyone of the previous claimsclaim`, wherein an amount of quercetin ranges between 25 and 100 mg.  
8. (Currently Amended) The methodComposition for use according to anyone of theprevious claimsclaimj2, wherein an amount of myricetin ranges between 25 and 50 mg.  
9. (Currently Amended) The methodComposition for use according to anyone of theprevious claimsclaim6, wherein an amount of genistein ranges between 0.01 and 600 mg; preferably between 1 and 100 mg, most preferably wherein the amount of genistein is about 12 mg.  
10. (Currently Amended) The methodComposition for use according to anyone of theprevious claimsclaim6, wherein an amount of berberine ranges between 0.01 and 1500 mg;preferably between 0.1 mg and 200 mg, most preferably wherein the amount of berberine is about 1 mg.  
11. (Currently Amended) The methodComposition for use according to anyone of theprevious claimsclaim7, wherein the composition is administeredpresent in a solid dosage form; such as a tablet, pill, lozenge, capsule, chewing gum,powder, or granule, preferably an orallydispersible lozenge or in an under the tongue dispersible tablet. 
12. (Currently Amended) The methodComposition for use according to any one of claims1 to 9claimv., wherein the composition is administeredpresent in a liquid dosage form; such as a drink or syrup. 
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13. (Original) Composition for use according to claim 12, wherein the composition comprises a viscosity controlling agent selected from acacia gum, tragacanth, alginic acid, carrageenan, locust bean gum, guar gum, gelatine, polyacrylate, methylcellulose, carboxymethylcellulose, xanthan gum, gellan gum, curdlan, dextran, pullulan, scleroglucan, or a combination thereof. 
14. (Currently Amended) The methodComposition for use according to claim 13, wherein the viscosity controlling agent is alginic acid.  
15. (Currently Amended) The methodComposition for use according to any one of claims13 and11claim13, wherein the viscosity controlling agent is present in an amount ranging from 0.05 - 10 wt.%, based on the total weight of the composition.  
16. (New) The method according to claim 14, wherein the viscosity controlling agent is present in an amount ranging from 0.05 - 10 wt.%, based on the total weight of the composition.  
17. (New) The method according to claim 2 wherein the method reinforces oesophagus wall barrier function in the patient.  
18. (New) The method according to claim 2, wherein the patient is a pregnant woman or a paediatric patient.  
19. (New) The method according to claim 2, the composition comprising quercetin (2- (3,4-dihydroxyphenyl)-3,5,7-trihydroxychromen-4-one) and myricetin (3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)-4H-1-benzopyran-4-one).  
20. (New) The method according to claim 2, wherein the composition comprises genistein (5,7-dihydro-3-(4-hydroxyphenyl)chromen-4-one) and/or berberine (5,6-dihydro-9,10- dimethoxybenzo [g]-1,3-benzodioxolo[5,6-a] quinolizinium).  

Determination of the scope and content of the prior art
Rao et al  descries on the protective effects of quercetin and alpha-tocopherol individually on experimental reflux oesophagitis in rats, thereby proposing inherently a method of treating gastroesophageal reflux disease . Quercetin is administred orally at a dose of 1OOmg/kg to rats of 140-160 g. The beneficial effects of quercetin and alpha-tocopherol on oesophageal mucosal damage are attributed to their antioxidant properties. The document discloses that the results of the study suggest that antioxidants could attenuate the severity of reflux oesophagitis and prevent the oesophageal mucosal damage  as in claims 3 and 17 and validate their therapeutic use in GERO. (see abstract ; page 234, a section of 2.1) 

The current invention, however, differs from the prior art in that the claimed 
myricetin and genistein and berberine with a specific amount , the patient being pregnant woman or a pediatric patient and the use of alginic acid in a specific amount in % are unspecified in the prior art.

Legge teaches a method of treating and/or preventing a gastrointestinal disease, disorder or condition in a subject, said method including the step of administering to said subject a therapeutically effective amount of the orally administrable formulation (see page 31, claim 19).
The use of Claim 14 or the method of Claim 19, wherein the gastrointestinal disease, disorder or condition is selected from the group consisting of candidiasis, celiac disease, Crohn' s disease, diarrhoea, constipation, ulcerative colitis, food allergy, food intolerance, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), intestinal dysbiosis, metabolic syndrome, ulcers, digestion disorders, malabsorption syndromes, gastritis, enteritis, gastroesophageal reflux, eosinophilic gastroenteritis as in claims 1-2 (partially), (see page 31, claim 20)
Also, it teaches that a formulation comprises flavonols such as quecetin, myricetin, genistein  (see page 7, lines 4  and 7) and a polyphenol such as berberine as in claims 5-6, 19-20 (see page 8 , line 32)

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as in claims 11-12, 15-16 (page 25, Product 1)

Wikipedia describes that alginate absorbs water quickly, which makes it useful as an additive in dehydrated products such as slimming aids, and it is also used in the food industry as a thickening agent for drinks, ice cream, cosmetics, as a gelling agent for jellies. Furthermore, alginate is used as an ingredient in various pharmaceutical preparations as in claims 13-14  (see page 3 , a section of uses).
Ascertainment of the difference between the prior art and the claims

1. The difference between the instant application and the applied art is that the
applied art do not expressly teach the claimed amount of myricetin and genistein and berberine , the patient being pregnant woman or a pediatric patient .

The difference between the current application and the applied Mitsuaki et al art is that the Rao et al  does not expressly teach  the claimed the claimed 
myricetin and genistein and berberine with a specific amount , eosinophilic gastroenteritis, the patient being pregnant woman or a pediatric patient and the use of alginic acid.  The deficiencies of the Rao et al are partially cured by the Legge and Wikipedia 

The difference between the current application and the applied Legge art is that the Legge does not expressly teach the claimed amount of quercetin,myricetin and genistein and berberine , the patient being pregnant woman or a pediatric patient and the use of alginic acid in a specific amount. The deficiencies of the Legge are partially cured by the Rao et al   and Wikipedia
The difference between the current application and the applied Wikipedia art is that the Wikipedia does not expressly teach the claimed amount of quercetin,myricetin and genistein and berberine , eosinophilic gastroenteritis , the patient being pregnant woman or a pediatric patient. The deficiencies of the Wikipedia are partially cured by the Rao et al   and Legge.

Resolving the level of ordinary skill in the pertinent art.

Regarding Claims 1, 8-10,  with respect to the lack of disclosing the claimed amount of myricetin and genistein and berberine, the primary refence, Rao et al does offer a generic guidance that quercetin is administered orally at a dose of 1OOmg/kg to rats of 140-160 g; from this, it is reasonable for the skilled artisan in the art who can figure out the proper dosage of each of  flavonols such as myricetin, genistein  (see page 7, lines 4  and 7) and the polyphenol such as berberine from Legge reference by routine experimentation.
Regarding Claims 4, 18,  with respect to the lack of disclosing the patient being pregnant woman or a pediatric patient, the prior art are silent about them. However, Rao et al  does teach indirectly that the skilled person would expect quercetin to be useful also in humans, such as pregnant women and pediatric patients. The most appropriate dose to be administerd for these groups of patients can be determined by the skilled person by routine experimentations, without involving an exercise of inventive step. Therefore, they are  considered to be obvious over the prior art. 


Considering objective evidence present in the application indicating obviousness or nonobviousness.
Rao et al expressly descries the method of treating gastroesophageal reflux disease by using quercetin and alpha-tocopherol individually
 through administering orally at its dose of 1OOmg/kg to rats of 140-160 g.
Similarly, Legge does teaches the method of treating and/or preventing a gastrointestinal diseases, such as gastroesophageal reflux, eosinophilic gastroenteritis as in claims 1-2 (partially), (see page 31, claim 20) by a means of using the formulation comprising quecetin, myricetin, genistein  (see page 7, lines 4  and 7) and berberine (see page 8 , line 32). Furthermore, Wikipedia does mention that  alginate can be used as a thickening agent and  a gelling agent  in various pharmaceutical preparations.
Rao et al and Legge are closely related to each other with respect to  the method of treating a gastrointestinal disease such as gastroesophageal reflux disease and/or eosinophilic gastroenteritis by using quercetin or quecetin, myricetin, genistein  and berberine. In addition, Wikipedia does suggerst that  alginate can be used as a thickening agent and  a gelling agent  in various pharmaceutical preparations.
So, if the skilled artisan in the art had desired to develop the formula containing quecetin, myricetin, genistein  and berberine in combining with alginic acid as a viscosity controlling agent efficiently, it would have been obvious to the skilled artisan in the art before the effective filing date of the claimed invention to be motivated to incorporate the teachings of Legge’s myricetin, genistein  and berberine with their corresponding proper amount  and Wikipedia’s alginic acid into the Rao et al method.
This is because the skilled artisan in the art would expect such a combined formula to be successful and feasible as guidance shown in the prior art. 

Conclusion
Claims 1-20 are rejected. 



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/TAYLOR V OH/Primary Examiner, Art Unit 1625                                                                                                                                                                                                        5/11/2025