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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04/08/2025 has been entered.
Priority
The present application was filed 07/28/2021. This application is claiming the benefit of provisional application No. 63/084,109, filed 09/28/2020.
Status of the Claims
Claims 1-14 are pending in the application. Claims 1 and 8 are amended. Claims 1-14 are examined below.
Withdrawn Objections/Rejections
The previous rejection of claims under 35 U.S.C.101 are withdrawn in response to Applicant’s amendments to the claims (the claims recite a step of administering, amounts to integration of a judicial exception into a practical application).
Status of the specification
A full text of any replacement paragraph with markings to show all the changes has been provided in the specification filed 04/08/2025.
The objection to the specification regarding the missing symbols indicating the use in commerce has been withdrawn due to the amendment of the specification.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825. This application contains a “Sequence Listing” as a PDF file (37 CFR 1.821(c)(2)) or as physical sheets of paper (37 CFR 1.821(c)(3)). A copy of the "Sequence Listing" in computer readable form (CRF) has been submitted; however, the content of the CRF does not comply with one or more of the requirements of 37 CFR 1.822 through 1.824, as indicated in the "Error Report" that indicates the "Sequence Listing" could not be accepted. Refer to attachment or document "Computer Readable Form (CRF) for Sequence Listing – Defective" dated 04/08/2025.
Required response – Applicant must provide:
A replacement "Sequence Listing" part of the disclosure, as described above in item 1); together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the replacement "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter and
An amendment to the specification to remove the “Sequence Listing previously submitted as a PDF file (37 CFR 1.821(c)(2)) or as physical sheets of paper (37 CFR 1.821(c)(3))
If the replacement "Sequence Listing" part of the disclosure is submitted according to item 1) c) or d) above, Applicant must also provide:
A CRF in accordance with 1.821(e)(1) or 1.821(e)(2) as required by 37 CFR 1.825(b)(6)(ii); and
Statement according to item 2) a) or b) above.
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.
The rejection under 35 U.S.C. 112(a) is maintained for reasons of record. The reasons are reiterated below:
Claims 1-14 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 claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is "undue" include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability in the art, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Regarding the nature of the claims, the present claim language broadly encompasses screening (claim 1) and early diagnosis of (claim 8) congenital vascular malformations, based on the biomarker ADAM30 (Applicant’s elected specie), as well as administering treatment (claims 1 and 8).
It is noted that MPEP 2164.03 teaches that "the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability of the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The amount of guidance or direction refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification.
In the present case, it appears that little is known in the prior art regarding the use of ADAM30 for screening for or detecting congenital vascular anomalies. Tan et al., US 20220112559A1, filed 08/12/2021 (see PTO-892, 09/27/2023) teaches serum levels of ADAM30 in people with port wine stains, lung cancer, and normal controls (Figure 22), however their results appear to show that there is no statistically significant difference between the control group and those with PWS/Lung cancer group or between the PWS and Lung cancer group. Drucker et al. (2013), “Pitfalls and limitations in translation from biomarker discovery to clinical utility in predictive and personalized medicine”, The EMPA Journal 4, 7, 10 pages (see PTO-892, 09/27/2023), teaches that the selection of useful biomarkers must be carefully assessed and depends on sensitivity (it should correctly identify a high proportion of true positive rate) and specificity (it should correctly identify a high proportion of true negative rate; Drucker, page 1, 5th paragraph, lines 3-8).
Although Tan appears to show ADAM30 detectable in serum of people with port wine stains, it is unpredictable (when considering what the art considers to be a good biomarker (Drucker)) that ADAM30 could be a biomarker usable for screening or early diagnosis of congenital vascular abnormalities such as Port Wine Stain. It is not predictable that ADAM30 is sensitive, as it does not appear to identify a high proportion of true positives, nor specific, because expression of ADAM30 is also changed in people with lung cancer, which are subjects not indicated to have congenital vascular abnormalities. It is unpredictable, based on what little is known in the art regarding the use of ADAM30 for screening for or detecting congenital vascular anomalies and therefore necessary to rely on the specification to provide more detail as to how to make and use the invention in order to be enabling.
There are no working examples in the originally filed specification. Although the specification at page 25, paragraph [0062], states that the inventors discovered in 2015, that a panel of molecules comprising ADAM30, have increased expression levels in Port Wine Stain (PWS) blood vessels (i.e., a tissue sample), there are no working examples or evidence that supports this. There is no indication in the originally filed specification that, SEQ ID NO 1 (ADMA30), for example is present or upregulated in liquid biopsy (liquid specimens) of those with congenital vascular anomalies (or PWS). Put another way, the specification only supports upregulation in PWS blood vessels relative to an expression level in a blood vessel sample obtained from a subject without PWS, therefore one would first have to identify the PWS blood vessel in order to obtain a sample with elevated ADAM30. As such one would have to already have known that the subject has PWS to carry out the method, i.e. the subject would have already been diagnosed and the method would be unpredictable in a subject that is asymptomatic, when the lesion is undetectable via diagnostic radiology and the malformation is invisible.
In addition, it is not readily predictable based on the prior art, that changes in ADAM30 (SEQ ID No. 1) levels in a subject would correlate with/be diagnostic for vascular abnormalities, such as PWS or any other vascular abnormalities. See rather, this marker was recognized in the art in relation to other diagnostic diseases or conditions, not related to vascular abnormalities.
For example, Letronne et al. (2016), “ADAM30 Downregulates App-Linked Defects Through Cathepsin D Activation in Alzheimer’s Disease”, EBioMedicine, 9, pages 278-292 (see PTO-892, 09/27/2023), teaches that ADAMS30 is under-expressed in the frontal cortex of Alzheimer’s disease cases (Letronne, page 282, ‘Results’, ‘4.1’, lines 1-7).
Further, Dong et al. (2022), “Systematic Analysis of Tumor Microenvironment Patterns and Oxidative Stress Characteristics of Endometrial Carcinoma Mediated by 5-Methulcytosine Regulators”, Oxidative Medicine and Cellular Longevity, 2022, Article ID 6431164, 25 pages (see PTO-892, 09/27/2023), teaches that ADAM30 is overexpressed in tumor tissues (Dong, page 1, Abstract, line 21).
Still further, Sharp et al., US20120015904A1, filed 07/14/2011 (see PTO-892, 09/27/2023), teaches a method for determining the occurrence of a transient ischemic attack (TIA; Sharp, page 1, paragraph [0008]) by determining the level of a plurality of TIA-associated biomarkers in a biological sample (Sharp, page 1, paragraph [0009], lines 4-5), wherein the list of biomarkers comprises ADAM30 (Sharp, page 12, line 18). Sharp further teaches that the expression of ADAM30 is upregulated (Sharp, page 36, line 50) in a sample of venous blood (liquid specimen) from patients with transient ischemia (Sharp, page 28, see paragraph [0177]).
Still further, Saeemann et al., WO2012146778A2, published 11/01/2012 (see PTO-892, 09/27/2023), teaches a method of determining the protein content of high density lipoprotein from a blood, serum, or plasma sample, wherein renal disease is indicated if the patient has at least one protein that is elevated compared to a healthy control, the list of proteins comprising ADAM30 (see Saeemann, page 2, 6th paragraph, line 1 to page 3, lines 1-10).
Based on the prior art discussed in detail above, and the lack of working examples that show or support SEQ ID NO. 1 is present and detectable in liquid samples of those with congenital vascular anomalies, or that it is upregulated in those with congenital vascular anomalies or diagnosed as having a congenital vascular malformation (claims 1 and 8), it is unpredictable that ADAM30 can be used as a biomarker for congenital vascular malformations (as at claim 1) or for early diagnosis of congenital vascular malformations (as at claim 8).
Given that it is known in the art that changes in ADAM30 levels can be indicative of a number of different conditions, e.g., Alzheimer’s disease, transient ischemia, and renal disease, and that there is no evidence supporting ADAM30 levels as a sensitive biomarker for congenital vascular malformations, it is not predictable that measuring changes in ADAM30 expression would specifically detect/indicate congenital vascular anomalies (claim 1), or diagnose PWS (claim 8).
The originally filed specification provides no guidance with regard to how make or use the claimed invention to indicate vascular anomalies.
In summary, the factors considered when determining if the disclosure satisfies the enablement regarding the prior art, establish that the specification fails to teach the ordinarily skilled artisan to make and use the claimed invention.
For all these reasons, the specification fails to indicate how to make or use the invention as claimed, without undue experimentation.
Claims 1-14 are further 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.
Regarding claims 1 and 8, the claims recite “establishing at least one expression level” and “establishing at least one increased expression level” which was not previously cited in the claims or the specification. Applicant recites in remarks filed 04/08/2025, page 6, that the present amendments are supported by, at least, paragraph [0066] of the specification. However, the specification at paragraph [0066] recites that the “inventors have found that a panel of molecules, including ADAM30 […] showed significantly increased expression levels”. The specification does not recite, in paragraph [0066] or elsewhere, a method of establishing at least one expression level nor a method of establishing at least one increased expression level as part of a method as presently claimed. The only references to an increased expression of biomarkers in relation to PWS in the originally filed specification is in reference to previous work by Applicants (e.g., para [0062]). Further, the specification does not describe an assay comprising establishing at least one expression level nor an assay comprising establishing at least one increased expression level. The newly recited limitations do not appear in the original disclosure.
Claims 2-7 and 9-14 depend on claims 1 and 8, respectively, and are therefore also rejected.
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 1-14 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1 and 8 as amended recite indefinite claim language.
As amended, prior to obtaining the sample step, the claim now recites the two “establishing steps”- it is not clear what is meant by “establishing at least one expression level for a presence” since establish expression level is quantitative (an amount/level) while “a presence” is qualitative- determining an expression level would already also necessarily establish a presence. This language is confusing as to what is and is not encompassed by the boundaries of the claim. For example, if it is Applicant’s intention to limit the claims to recite a step of determining an expression level, then it would necessarily follow that this also indicates presence, that the claim would not encompass to steps, one of establishing expression level and one of establishing a presence of the biomarker.
Regarding the second establishing step, “at least one increased expression level for the presence of the at least one biomarker”, this language suggests a given “at least one” biomarker could have more than one expression level (by reciting the article “a”), which presumably a given sample from a subject is going to exhibit (at a single measurement time) one level for the at least one biomarker, not different possible increased levels. As such, the language “at least one increased expression level”, at the second “establishing” step is also indefinite because it is not clear what is being claimed or how there can be more than one “increased expression of the at least one biomarker” determined from the first establishing step.
The claim further, after the first two establishing steps, recites “screening the biological sample for the at least one biomarker”. However, the claim already recites the two active steps of “establishing” both of which read as “screening steps” (i.e., one is screening in that it establishes at least one expression level, the other is screening in terms of establishing “increased expression”. Therefore, the recited language at the “screening” step is indefinite because it is not clear if the screening step recited after obtaining the sample is part of or distinct from the two prior recited establishing steps. The claim after the “screening” step, further recites a step of “finding...at least one increased expression”, which is also confusing and considered to be indefinite because the claim already achieved a determining of increased expression based on the second “establishing” step. The recited language is indefinite because metes and bounds of what is encompassed are unclear because the amendments to the claims raise confusion as to how many active method steps are performed, and what exactly they are.
Claims 1 and 8 are further indefinite for the claim language “a genetic sequence identified in SEQ. ID NOS. 1-8” because sequence numbers 1-8 are protein sequences, not genetic (gene) sequences.
Further, regarding the recited language “sequence identified in SEQ ID NOS. 1-6”, this language is indefinite because it raises a question as to what is and is not encompassed by the boundaries of the claim limitation. Specifically, the recited language “sequence identified in SEQ ID NOS. 1-6” means a sequence that is any of these sequences, but also any sequence that is a smaller peptide sequence that is contained within these SEQ ID NOS. The claims are indefinite because it is not clear if they are limited to biomarkers consisting of this sequence or if the biomarker can be these sequences and any smaller peptide sequences from within each of the claimed sequences.
Claims 2-7 and 9-14 depend on claims 1 and 8, respectively, and are therefore also rejected.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
The double patenting rejection is maintained for reasons of record reiterated below.
US 12,006,550 B2
Claims 1-14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 2 of U.S. Patent No. 12,006,550 B2 in view of Gao et al. Topical axitinib suppresses angiogenesis pathways induced by pulsed dye laser. British Journal of Dermatology. 2015 Mar 1;172(3):669-76 (of record; see PTO-892, 08/22/2024). Although the claims at issue are not identical, they are not patentably distinct from each other because U.S. Patent No. 12,006,550 B2 similarly cites a method for screening for congenital vascular anomalies by screening for SEQ ID No. 1 (ADAM30).
Regarding claim 1, see U.S. Patent No. 12,006,550 B2 claims 1 and 2 teach a method for detecting congenital vascular anomalies by obtaining at least one body fluid sample from a sample, introducing at least one antibody configured to bind ADAM30 (screening), wherein binding of the antibody to at least one biomarker forms an assay (finding at least one biomarker; see claim 1). U.S. Patent No. 12,006,550 B2, claim 1 further teaches wherein the presence of the at least one biomarker in the body fluid, whether analyzed in vivo or in vitro (establishing at least on expression level) and still further teaches wherein formation of the assay determines when there is an increase in ADAM30 (establishing at least one increased expression level). U.S. Patent No. 12,006,550 B2 further teaches that the biomarker has a genetic sequence of SEQ. ID No. 1 (ADAM30; see US 12,006,550 B2 claim 2). Claim 1 further teaches administering a therapeutically effective amount of a therapeutic agent to treat the vascular disease or disorder.
Claims 1 and 2 fail to teach administering a Src Inhibitor to treat the at least one congenital vascular malformation.
Gao teaches that after treatment of port wine stain lesions with pulsed dye laser blood vessels reoccur in most patients and that a better outcome might be achieved with pulsed dye laser combined with the administration of anti-angiogenesis agents (Gao, page 670, see 2nd paragraph). Gao further teaches that application of axitinib can systematically suppress early stages of angiogenesis via inhibition of a pathway comprising Src homology 2 domain containing transforming protein-1/mitogen-activated protein kinase kinase/ERK pathway cascades (Gao, page 669, ‘Abstract’, see ‘Conclusions’). Gao further teaches that multiple signaling pathways are generally activated during pulse dye laser induced angiogenesis and therefore a multitarget inhibitor, such as axitinib may produce a better effect (Gao, page 670, 2nd paragraph, lines 18-24).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the method of U.S. Patent No. 12,006,550 B2 by administering a therapeutic agent that is a src inhibitor, because of the teaching of Gao that axitinib, which inhibits pathways involving src, can systematically suppress early stages of angiogenesis in treated port wine stain lesions.
One having ordinary skill in the art would have a reasonable expectation of success, because both U.S. Patent No. 12,006,550 B2 and Gao teach treatment of port wine stain lesions.
Regarding claim 2, see US 12,006,550 B2 claim 1, obtaining at least one body fluid sample (liquid biopsy).
Regarding claim 3, see US 12,006,550 B2 claim 1, obtaining at least one body fluid sample (body fluids).
Regarding claims 4-7, US 12,006,550 B2 claims 1 and 2 teach the method substantially as claimed. Regarding the additional limitations of “wherein the at least one congenital vascular malformation comprises port wine stain” (claim 4), “wherein the at least one congenital vascular malformation is symptomatic or asymptomatic” (claim 5), “wherein screening is administered prior to vascular lesions growing to a detectable size” (claim 6), and “wherein the at least on congenital vascular malformation is visible or invisible” (claim 7), MPEP in 2111.04 states that the broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met. Considering that claims 4-7 do not present additional active steps and the art teaches the method as claimed, the art meets the limitation of the claims.
Regarding claim 8, see US 12,006,550 B2 claims 1 and 2 teach a method for detecting congenital vascular anomalies, which comprises the steps comprised by the molecular assay and as such the method of US 12,006,550 B2 claims 1 and 2 teaches the assay as claimed in claim 8. US 12,006,550 B2 claims 1 and 2 teach determining the presence of a biomarker (screening) in a body fluid (biological sample wherein the presence of the at least one biomarker indicates the presence of at least one vascular malformation (see claim 1) and the biomarker has a genetic sequence of SEQ. ID No. 1 (ADAM30; see US 12,006,550 B2 claim 2). U.S. Patent No. 12,006,550 B2, claim 1 further teaches wherein the presence of the at least one biomarker in the body fluid, whether analyzed in vivo or in vitro (establishing at least on expression level) and still further teaches wherein formation of the assay determines when there is an increase in ADAM30 (establishing at least one increased expression level). The limitation “wherein the molecular assay is administered prior to vascular lesions growing to a size detectable” fails to add any additional active steps to the claim, rather the limitation is merely limiting the subject’s themselves (to those with no lesions detectable by radiology). In the present case, US 12,006,550 B2 is a method of detecting, and further treating (US 12,006,550 B2 claim 1), it would have been further obvious to have applied the method as early as possible, for example prior to lesions growing to a detectable size in an effort to treat and prevent the lesion.
Claims 1 and 2 fail to teach administering a Src Inhibitor to treat the at least one congenital vascular malformation.
Gao teaches that after treatment of port wine stain lesions with pulsed dye laser blood vessels reoccur in most patients and that a better outcome might be achieved with pulsed dye laser combined with the administration of anti-angiogenesis agents (Gao, page 670, see 2nd paragraph). Gao further teaches that application of axitinib can systematically suppress early stages of angiogenesis via inhibition of a pathway comprising Src homology 2 domain containing transforming protein-1/mitogen-activated protein kinase kinase/ERK pathway cascades (Gao, page 669, ‘Abstract’, see ‘Conclusions’). Gao further teaches that multiple signaling pathways are generally activated during pulse dye laser induced angiogenesis and therefore a multitarget inhibitor, such as axitinib may produce a better effect (Gao, page 670, 2nd paragraph, lines 18-24).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the method of U.S. Patent No. 12,006,550 B2 by administering a therapeutic agent that is a src inhibitor, because of the teaching of Gao that axitinib, which inhibits pathways involving src, can systematically suppress early stages of angiogenesis in treated port wine stain lesions.
One having ordinary skill in the art would have a reasonable expectation of success, because both U.S. Patent No. 12,006,550 B2 and Gao teach treatment of port wine stain lesions.
Regarding claim 9, see US 12,006,550 B2 claim 1.
Regarding claim 10, see US 12,006,550 B2 claim 1.
Regarding claims 11-14, as discussed previously in detail above, MPEP in 2111.04 states that the broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met. Considering that claims 11-14 do not present active steps and the art teaches the method as claimed, the art meets the limitation of the claims.
Response to Arguments
Applicant's arguments filed 04/08/2025 have been fully considered but they are not persuasive. Applicant argues in response to the rejections under 35 U.S.C. §112 that the claims have been amended to further explain the treatment technique via use of a base line and increased expression level for gauging the presence of the claimed biomarkers to overcome the rejection. This argument is not persuasive.
The rejection under 35 U.S.C. §112(a) is maintained because the claims contain 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. As explained previously in detail above in the rejection under 35 U.S.C. §112(a), based on the prior art discussed and the lack of working examples it is unpredictable that ADAM30 can be used as a biomarker or for early diagnosis of congenital vascular malformations. Given that it is known in the art that changes in ADAM30 levels can be indicative of a number of different conditions and that there is no evidence supporting ADAM30 levels as a specific biomarker for congenital vascular malformations, it is not predictable that a method measuring changes in ADAM30 expression would specifically detect/indicate congenital vascular anomalies (claim 1), or that an assay would diagnose congenital vascular malformation (claim 8) and the originally filed specification provides no guidance with regard to how to make or use the claimed invention to indicate vascular anomalies without undue experimentation.
Regarding the amendments of claims 1 and 8, the establishing of at least one expression level and one increased expression level are limitations not previously recited in the claims or the specification as part of a claimed method. As a result, see new grounds of rejection further set forth above under 35 U.S.C. 112.
The specification also does not provide any evidence that ADAM30 is a sensitive biomarker for congenital vascular malformations or that it can distinguish patients with this condition from others which may suffer from other diseases that result in elevated ADAM30 levels (see above). For these reasons, the previous rejection under 35 U.S.C. 112(a) is maintained.
Regarding remarks to the rejection of claims under 35 U.S.C. 101, see as indicated in detail previously above, the rejection is withdrawn in response to Applicant’s amendments to the claims.
For all the reasons above, the arguments are not persuasive.
Communication
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/STEFANIE J. KIRWIN/Examiner, Art Unit 1677
/ELLEN J MARCSISIN/Primary Examiner, Art Unit 1677