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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 28 July 2025 has been entered.
Response to Amendment
Claims 15 and 20 have been amended and claims 1-14 and 23 have been canceled. Claims 15-22 are currently pending and under consideration in the instant Office action.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Any objection or rejection of record which is not expressly repeated in this action
has been overcome by Applicant’s response and withdrawn.
Applicant’s arguments filed 28 July 2025 have been fully considered but are not found to be persuasive.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01 July 2025 has been considered by the examiner.
Drawings
The replacement drawings filed 01 July 2025 are still objected to because they do not comply with 37 CFR 1.84 (a)(1) which requires that black and white drawings use India ink, or its equivalent that secures solid black lines and 37 CFR 1.84 (l) which requires that all drawings must be made by a process which will give them satisfactory reproduction characteristics. Every line, number, and letter must be durable, clean, black, sufficiently dense and dark, and uniformly thick and well-defined. The weight of all lines and letters must be heavy enough to permit adequate reproduction. All of the Figures fail to meet the standards of 37 CFR 1.84(a)(1) and/or 37 CFR 1.84(l).
Several of the figures do not have solid black lines and several of the figures do not have lines, numbers and letters which are black, sufficiently dense and dark and uniformly thick and well-defined. Additionally, because these requirements are not met, the lines/letters do not permit adequate reproduction.
The Figures have the exact same issues as noted in the previous Office actions.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim 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.
Claims 15-19 stand 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(s) 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.
Claim 15 is directed to a method of treatment comprising administering an antibody (or anti-adrenomedullin antibody fragment to a subject, wherein said subject has a level of mature adrenomedullin below a predetermined threshold level (or based on a ratio of mature adrenomedullin to other forms of adrenomedullin). Claim 15 defines the antibody/fragment as “produced by a process” wherein the process includes generation of an antibody by immunizing a mammal with mature ADM or screening for antibodies against adrenomedullin from an antibody gene library.
The instant specification fails to provide an adequate written description for an antibody or antibody fragment obtained by the recited processes as well as failing to describe an antibody or antibody fragment which comprises as few as one CDR from each of the heavy and light chains of a given antibody.
First, the instant specification fails to provide an adequate written description for an “anti-adrenomedullin antibody fragment” because “antibody fragment” encompasses any fragment of an antibody which binds to adrenomedullin. There is no requirement that the fragment of the claims actually bind to adrenomedullin. The instant specification fails to describe such fragments and one of ordinary skill in the art would not be able to envision such fragments as they could encompass any di-peptide which could be found in any antibody that binds to adrenomedullin.
Next, while the art before the effective filing date of the claimed invention teaches some antibody which bind mature adrenomedullin, the prior art is lacking with regard to binding “to the N-terminal part (aa 1-21) of adrenomedullin” as recited in claim 15. Furthermore, claim 15 also requires that the antibody “has an amino acid sequence which is identical to an antibody produced by a process” which includes immunization of a mammal with an antigen, fusing splenocytes, culturing cells and screening for cells expressing antibody or fragment that binds to the N-terminal part (aa 1-21) of adrenomedullin OR screening a gene library to identify antibodies/fragments. Claim 15 does not provide any structure or amino acid sequence what so ever for the antibody/fragment in the claimed method. Neither the prior art nor the instant specification teach a representative number of species falling within the scope of the recited genus and neither the prior art nor the instant specification provides any structure/function correlation with regard to antibody structure and ability to bind the N-terminal part of adrenomedullin.
Vas-Cath Inc. V. Mahurkar, 19 USPQ2d 1111, states that Applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention, for purposes of the written description inquiry, is whatever is now claimed (see page 1117). A review of the language of the claims indicate that these claims are drawn to methods which administer anti-adrenomedullin (ADM) antibodies or anti-adrenomedullin antibody fragments.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus. Regents of the University of California v. Eli Lilly & Co., 119 F3d 1559, 1569, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997). In Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412), the court held that a generic statement which defines a genus of nucleic acids by only their functional activity does not provide an adequate written description of the genus. The court indicated that, while applicants are not required to disclose every species encompassed by a genus, the description of the genus is achieved by the recitation of a representative number of species falling within the scope of the claimed genus. At section B(1), the court states, “An adequate written description of a DNA ... requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.”
The specification, beginning at page 31, generically describes antibodies. The disclosure (beginning at page 38) teaches an embodiment of anti-ADM antibody with a defined CDR structure (the portions of the antibody which are responsible for binding antigen). The specification does not teach any anti-ADM antibody fragments.
The specification discloses the reduction to practice of antibodies which comprise the following CDRs:
heavy chain CDRs:
SEQ ID NO: 1 GYTFSRYW,
SEQ ID NO: 2 ILPGSGST,
SEQ ID NO: 3 TEGYEYDGFDY;
and light chain CDRs:
SEQ ID NO: 4 QSIVYSNGNTY,
RVS,
SEQ ID NO: 5 FQGSHIPYT.
However, the claims encompass many more binding structures which are not further described.
Thus, given the level of skill and knowledge and predictability in the art, those of skill in the art would not conclude that the applicant was in possession of the genera of ADM-binding proteins recited in the claimed methods based on disclosures set forth above. Claim 15 does not provide any guidance on the structure of the antibody/fragment that must be present in order for antigen.
"A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when ... the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).
For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly.
Further, it is not sufficient to define the genus solely by its principal biological property, because an alleged conception having no more specificity than that is simply a wish to know the identity of any material with that biological property. Per the Enzo court's example, (Enzo Biochem, Inc. v. Gen-Probe Inc., 63 USPQ2d 1609 (CA FC 2002) at 1616) of a description of an anti-inflammatory steroid, i.e., a steroid (a generic structural term) couched "in terms of its function of lessening inflammation of tissues" which, the court stated, "fails to distinguish any steroid from others having the same activity or function" and the expression "an antibiotic penicillin" fails to distinguish a particular penicillin molecule from others possessing the same activity and which therefore, fails to satisfy the written description requirement. Similarly, the function of the variant as claimed does not distinguish a particular variant from others having the same activity or function and as such, fails to satisfy the written-description requirement. Applicant has not disclosed any relevant, identifying characteristics, such as structure or other physical and/or chemical properties, sufficient to show possession of the claimed genus. Mere idea or function is insufficient for written description; isolation and characterization at a minimum are required. A description of what a material does, rather than what it is, usually does not suffice. (Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the genus of molecules being administered in the claims, which are “anti-adrenomedullin (ADM) antibodies and anti-adrenomedullin antibody fragments”. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the genus. The specification does not clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed (see Vas-Cath at page 1116).
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
Response to Arguments
Applicant asserts at page 8 of the response that product by process claiming methodology was used in recently issued patent 12,247,988 and asserts that this is evidence that this kind of product by process claiming is acceptable to the USPTO. Applicant’s argument has been fully considered, but is not found persuasive. First, each application is examined on its own merits and the Examiner will not comment on the prosecution of another patent application. The rejection was not made because product by process claims are not issued by the USPTO but rather, because the instant claims lack an adequate written description for the claimed subject matter as explained above. The claims are not directed to method which utilizes a singular product, but rather to a method which utilizes a genus of antibodies or binding fragments.
Applicant argues at page 8 of the response that MPEP § 2163(II)(A)(3)(a)(i) addresses claims which define the antibodies by product by process and states that applicants have satisfied written description.
Applicant's argument has been fully considered, but is not found persuasive.
MPEP § 2163(II)(A)(3)(a)(i) is directed to “claim drawn to a single embodiment or species”. The instant claims encompass a genus of antibodies/fragments. Furthermore, the methods which are recited do not result in a specified antibody/fragment as the processes result in a host of antibodies which then must be screened for their ability to bind the specified target. Therefore, the recitation of the processes in claim 15 do not actually appear to produce a specific species/product but rather a genus of compounds which then would require further screening and selection to arrive at a potential compound to be used in the claimed method. The MPEP at the section cited by Applicant goes on to state that “the requirement may not be satisfied where it is not clear that the acts set forth in the specification can be performed, or that the product is produced by that process’.
Applicant refers to “the Amgen decision” and alleges it is “also in the above paragraph” at page 9 of the response. None of the above paragraphs refer to an Amgen decision and it is not clear which Amgen decision Applicant is citing. Applicant may possibly be referring to Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991), but this decision does not support Applicant’s position. The Federal Circuit in this case held that if an inventor is “unable to envision the detailed constitution of a gene so as to distinguish it from other materials…conception has not been achieved until reduction to practice has occurred”, Amgen, Inc. v. Chugai Pharmaceutical Co, Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). Attention is also directed to the decision of The Regents of the University of California v. Eli Lilly and Company (CAFC, July 1997) wherein is stated: The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention.
Applicant may also be referring to Amgen Inc. v. Sanofi, Aventisub LIC, No. 2017-1480 (Fed. Cir. 2017) which also does not support Applicant’s position. In this decision, the court held that adequate written description of a newly characterized antigen alone is not adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional.
Also note that the written description provision of 35 U.S.C. 112 is severable from its enablement provision, Ariad Phar., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010; see also Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1876 (Fed. Cir. 2011). That is, while it might be possible to produce a particular antibody, mere instructions as to how to produce said antibody do not provide an adequate written description of said antibody.
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
Applicant’s argument at page 10 with regard to the previous rejection of the claims for reciting “antibody fragment” has been avoided by the amendment to the claims (this was addressed in the Advisory action mailed 25 June 2025 as it was stated that this portion of the rejection would be withdrawn).
Applicant argues at page 11 of the response that claim 15 does not need to provide any structure for the antibody/fragment used in the claimed method because the claims are relying on a product-by-process recitation. Applicant asserts that the case law cited in the Office action does not relate to product-by-process claims and again cites MPEP § 2163(II)(A)(3)(a)(i).
Applicant’s argument has been fully considered, but is not found persuasive. MPEP § 2163(II)(A)(3)(a)(i) is directed to “claim drawn to a single embodiment or species”.
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The process which is recited in claim 15 does not produce a singular product. The process would produce a multitude of antibodies which then would need to be screened to select for an antibody which possessed the necessary functionality required. This is not a product-by-process recitation as the process does not produce a singular product. The decision of The Regents of the University of California v. Eli Lilly and Company (CAFC, July 1997) stated: The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention.
At the bottom of page 12, Applicant asserts that the rejection is misreading MPEP § 2163(II)(A)(3)(a)(i). Applicant then cites to a portion of this section of the MPEP. For illustrative purposes, this is a screenshot of the relevant portion of the MPEP:
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As can be clearly seen, this portion of the MPEP has the header “For Each Claim Drawn to a Single Embodiment or Species”. The portion Applicant is referring to is the second full paragraph in this section. Clearly, this section of the MPEP is referring to claims which are drawn to a “Single Embodiment or Species”. The method of claim 15 is not utilizing a single embodiment/species of antibody/antibody fragment.
Applicant asserts at the bottom of page 13 that this is “perfectly consistent with the Amgen decision (also in the above paragraph) which held, that “a partial structure without additional characterization of the product may not be sufficient to evidence possession of the claimed in invention”. Applicant asserts that Amgen was directed to an antibody and where the antibody was claimed by its antigen and that Amgen’s holding and reasoning had nothing to do with a product-by-process claim. Applicant’s argument has been fully considered, but is not found persuasive. The instant claim which attempts to define the antibody/antibody fragment by a product-by-process recitation lacks written description because the process which is recited does not produce a “product”, but rather a genus of molecules which then need to be screened. Amgen is completely on point, because the claims are in fact defining the antibody/antibody fragment by what it binds because the claim is relying on the use of the antigen to make an antibody. But, the process of making the antibody as recited does not result in an antibody with a given structure because the process does not result in a singular product. Because it does not result in a singular product, the reliance on the product-by-process recitation for providing an adequate written description for the element of the claims is misplaced.
Applicant argues at page 15 of the response that “MPEP § 2163(II)(A)(3)(a)(i) even provides a specific comparison between product claims and product by process claims on this specific issue”. Applicant is conflating two different sections of the MPEP as the quoted section is from MPEP § 2163(II)(A)(3)(a)(ii).
Applicant asserts that the MPEP is clear that the “single species” rule only applies to product claims at page 15 of the response. Applicant’s argument has been fully considered, but is not found persuasive. No support can be found to support Applicant’s conclusion.
Claims 15-22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claims 15 and 20 are directed to a method of treatment comprising “treating a subject suffering from dementia or Alzheimer’s disease” by administering an antibody (or fragment) to a subject suffering from dementia or Alzheimer’s disease, wherein said subject has a level of mature adrenomedullin below a predetermined threshold level (or based on a ratio of mature adrenomedullin to other forms of adrenomedullin). Dependent claims recite threshold levels and define a sample.
The claims fail to indicate what condition/disease is being treated by the claimed method. While the claims have been amended to recite that the method of treatment comprises “treating a subject suffering from dementia or Alzheimer’s disease” and the claim additionally recites that the subject is suffering from dementia or Alzheimer’s disease, this does not necessarily mean that the claimed method is directed to or limited to treatment of dementia or Alzheimer’s disease. The “method of treatment” could be directed to treating some other condition in the subject and the subject population is merely limited to one that is suffering from dementia or Alzheimer’s disease.
The instant specification fails to teach any methods of treatment which comprise administration of an antibody or antibody fragment to adrenomedullin in which the subject has a level of adrenomedullin below a predetermined threshold or below 15 pg/ml (claims 17 and 21). The specification speculates that administration of N-terminal anti-ADM antibodies “may help to repair the leaky or damaged blood brain barrier” in subjects with dementia (see page 13 of the specification at lines 15-19). However, the instant specification provides no evidence that administration of anti-ADM antibodies which bind to the N-terminal part of adrenomedullin to any subject or to a subject who has a level of adrenomedullin below 15 pg/ml and any therapeutic benefit at all that relates to a “treatment” in a subject with dementia or Alzheimer’s disease.
The prior art of Letizia et al. (1998, Blood Pressure, 7:1, 19-23, DOI: 10.1080/080370598437529) states that normal levels of plasma adrenomedullin are 13.2 +/- 6.2 pg/ml. The prior art of Lupo et al. (Investigative Ophthalmology & Visual Science May 2004, Vol. 45, 5113) states that in the average population, adrenomedullin plasma concentration ranges between 13.7 +/- 6.1 pg/ml. The claimed method requires “treatment” of a patient the level of adrenomedullin is below 15 pg/ml. However, based on the prior art, patients with levels of adrenomedullin below 15 pg/ml would be considered normal subjects. One of ordinary skill in the art would not consider administration of an antibody/fragment to a subject to be a “treatment” when the subjects which are encompassed by the claims with levels of adrenomedullin below 15 pg/ml have adrenomedullin levels which would be considered normal and therefore, not in need of treatment. Additionally, the claims fail to specify what condition is being treated. The claims are not enabled for treating a subject who has a plasma adrenomedullin level that is considered to be normal according to the prior art because such subjects would not be in need of treatment. A normal subject is not one that is in need of treatment.
While limitations are not read into the claims, the claims are to be read in the light of the specification. Based on the disclosure of the specification, it would be fair to assume that the instant claims are intended to be methods of treating dementia and/or Alzheimer’s disease. However, the instant specification fails to provide any evidence that administration of antibodies which bind to N-terminal adrenomedullin would result in any therapeutic benefit for dementia or Alzheimer’s disease. As pointed out above, the “threshold” value which is recited in the claims is considered by the prior art to encompass normal levels of adrenomedullin in the population. While the specification asserts that low levels of adrenomedullin may be an indicator of dementia, the instant specification fails to establish that adrenomedullin is causative for the condition of dementia or is involved in the disease’s development and progression such that administration of antibodies which bind adrenomedullin would provide a treatment. While a protein may be a marker for a given condition, the association of a marker with a given condition does not establish that the marker is causative or implicated in progression of the condition and therefore, a therapeutic target for a given condition. In so far as the claims encompass a treatment for dementia, the state of the prior art is clearly unpredictable as there is no known cure for dementia although there are some treatments that can help with symptoms such as cholinesterase inhibitors. However, there are no current medications that stop, slow down or reverse dementia and there are clearly no antibody therapies for such. In light of the fact that at the time of the effective filing date of the claimed invention actual treatments for dementia were lacking, one of ordinary skill in the art would find it unpredictable that administration of an antibody which binds to the N-terminal part of adrenomedullin would result in the treatment of dementia or Alzheimer’s disease, absent evidence to the contrary.
Response to Arguments
Applicant arguments at page 7 of the response are directed to comments made in the advisory action. These comments were made in response to Applicant’s arguments in the after-final response. Briefly, Applicant states that the advisory action “appears to present reasoning why bio-ADM must be the (sole) cause of Alzheimer’s progression in order to make treatment with an anti-ADM antibody acceptable”. Applicant’s interpretation of Examiner statements made in the advisory action are inaccurate. The statements in the advisory action were related to the fact that the threshold values of ADM being relied upon for determination of dementia and Alzheimer’s disease encompass normal values of ADM in the population and that low adrenomedullin levels have not been established to be causative or implicated in the progression of dementia or Alzheimer’s disease in the instant specification.
Applicant mischaracterizes the Examiner’s statement in the advisory action regarding Alzheimer’s medication. The advisory clearly stated in response to Applicant’s assertion that the rejection did not allege any reason to doubt the objective truth of the statements with regard to the treatment of dementia or Alzheimer’s disease, “the state of the prior art is such that there are no current medications that stop, slow down or reverse dementia and there are clearly no antibody therapies for such and therefore, one of ordinary skill in the art would find it unpredictive that administration of an antibody which binds to the N-terminal part of adrenomedullin would result in the treatment of dementia”. Applicant’s reliance on recently approved antibodies (aducanumab and lecanemab which bind amyloid) does not negate the statement in the advisory action as the disclosure of Cummings et al. is not considered “the state of the prior art” as Cummings et al. has a publication date of 2024, which is 6 years after the priority date of the claimed invention.
Applicant asserts at page 7 of the response that bio-ADM is increased by the administration of anti-ADM antibodies binding to the N-terminal part of ADM. Applicant asserts that Geven et al. (2018, Fig. 3) “explains the mode of action via active ADM” in rebuttal of the statements in the advisory action questioning the ability of antibodies to increase the amount of active ADM.
First, Applicant has submitted two references for which Geven is the first author and both references have a publication date of 2018. Secondly, both references have a Figure 3. It is requested that in the future, Applicant make clear what evidence is being relied upon so that the Examiner may be able to identify with certainty what evidence is to be reviewed. The Examiner assumes that the SHOCK review article is the evidence that is being relied upon by Applicant.
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This figure does answer the question raised by the Examiner in the Advisory action of whether ADM would be bioactive when bound to an antibody that binds to the N-terminal region of ADM.
Applicant asserts at page 10 of the response that claims 15 and 20 have been amended to “explicitly require the step of “treating a subject suffering from dementia or Alzheimer’s disease”” and that this amendment should avoid the issue of not knowing what is being treated. Upon reconsideration of the amendment, it is concluded that the current amendment does not explicitly state that the claimed method is for treating dementia or Alzheimer’s disease. The claims are clearly treating a very specific patient population and that patient population is suffering from dementia or Alzheimer’s disease but the preamble of the claim is a generic “method of treatment”. While the patient is “suffering from dementia or Alzheimer’s disease”, there is no positive recitation that what is being administered is intended to treat the dementia/Alzheimer’s disease. It is suggested that the claim positively recite what is being treated.
Applicant argues at pages 16-17 of the response that the examiner has the initial burden to establish a reasonable basis to question the enablement provided for the claimed invention. Applicant’s argument has been fully considered but is not found persuasive. A reasonable basis was provided in the rejection of the claims in the Office action mailed on 01 April 2025. Briefly, the specification provides no methods of treatment which administer an antibody and the specification merely speculates that N-terminal anti-ADM antibody may help to repair leaky/damaged blood brain barrier. The specification did not administer an N-terminal anti-ADM antibody to any subject to arrive at any therapeutic outcome which would be suggestive of a treatment in subjects suffering from dementia/Alzheimer’s disease. Additionally, the state of the prior art was determined to be unpredictable in view of the lack of treatments available at the time of the instant invention. Therefore, the required burden was met.
Applicant argues at page 17 of the response that administration of anti-ADM antibodies binding to the N-terminal part of ADM increases the concentration of bio-ADM in the blood. Applicant references Nagata et al. (2019) as showing that administration of PEG-ADM I effective in mice in vascular dementia and therefore, there is no objective reason to doubt that the claims do treat dementia or Alzheimer’s disease.
Applicant’s arguments have been fully considered, but are not found persuasive. Nagata et al. (2019) administer polyethylene glycol-conjugated human adrenomedullin to a four-vessel occlusion model rat. Nagata et al. conclude that PEG-AM is a possible therapeutic agent for the treatment of ischemic brain injury or vascular dementia. The four-vessel occlusion model in rats is a model for studying global ischemia and stroke-related brain damage. It is not an art recognized model for studying Alzheimer’s Disease or dementia, in general. The instant claims are not limited to vascular dementia and PEG-AM is not equivalent to anti-ADM antibodies which bind to the N-terminal part of ADM.
The art recognizes a number of different types of progressive dementia including Alzheimer’s disease, vascular dementia, Lewy body dementia, frontotemporal dementia and mixed dementia. The art also recognizes that other conditions can be linked to dementia which include Huntington’s disease, traumatic brain injury, Creutzfeldt-Jakob disease and Parkinson’s disease. Dementia is also associated with invention/immune disorders, metabolic/endocrine conditions, low levels of nutrients, medicine side effects, subdural bleeding, brain tumors and normal-pressure hydrocephalus, but in these situations the dementia is normally reversable. There is no teaching in the instant specification or in the prior art of record that would suggest adrenomedullin is involved in the progression of dementia in all of these conditions. There is no teaching or suggestion in the prior art that would lead one of ordinary skill in the art before the effective filing date of the claimed invention that increasing the amount of adrenomedullin in a subject by administration of an antibody which binds the N-terminus of adrenomedullin would provide a therapeutic benefit for subjects with any type of dementia, including Alzheimer’s disease. In fact, the prior art contemplates that elevated levels of adrenomedullin in the brain contribute to the pathogenesis of Alzheimer’s disease. Ferrero et al. (Mol. Neurobiol. (2018) 55:5177-5183) conclude “from our present observations in AD postmortem tissue, it might be inferred that therapeutical approaches aimed at reducing AM/PAMP levels may constitute a novel path to prevent/delay AD neurodegeneration” and that “ADM gene products might represent novel pathological features contributing to perturbations of neuronal maintenance and synaptic function in AD, and their pharmacological inhibition may constitute a novel approach to the treatment of AD” (see page 5182). The instant specification fails to provide any evidence that administration of an antibody which binds to the N-terminus of adrenomedullin would provide any therapeutic effect for the treatment of Alzheimer’s disease or any other form of dementia which is not vascular dementia. The evidence which is presented for vascular dementia is not predictive of other forms of dementia as the animal model is one of global ischemia and stroke-related brain damage and not all forms of dementia are caused by ischemia. Furthermore, the prior art teaches that adrenomedullin levels are elevated in the brain of subjects with Alzheimer’s disease and suggests that inhibition of adrenomedullin may provide a treatment for Alzheimer’s disease. Therefore, the instant claims are not enabled for treating dementia or Alzheimer’s disease as currently claimed.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Christine J Saoud whose telephone number is (571)272-0891. The examiner can normally be reached M-F, 6am-2:30pm.
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/Christine J Saoud/Primary Examiner, Art Unit 1645