DETAILED CORRESPONDENCE
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 4/12/2025 has been entered.
Election/Restrictions – Retained for the Record
Applicant’s election without traverse of Group III, originally claims 103-110, in the reply filed on 12/19/21 is acknowledged, including amendment to claim 103 to indicate SEQ ID NO:4 is the elected peptide species for Group III.
Also acknowledged is Applicant’s presentation of those Group III claims with further amendments including new claims 111-118.
As indicated in the 8/6/21 Restriction Requirement, linking claims 89, 90 and 91 are examined with the elected Group III, this notwithstanding the “withdrawn” designation in the 12/19/21 claim set.
Claims 72 and 92-102 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/19/21.
Applicant 12/19/21 election did not respond to the additional species election requirements pertaining to species of ion (this moot given cancellation of claim 109 and withdrawn upon reconsideration notwithstanding Applicant’s 6/21/22 Remarks page 8) nor the additional species election for surgical procedure. In a telephone interview to Applicant Attorney Constantine Linnik on 1/10/22, Attorney Linnik elected endoscopic mucosal resection (EMR) (telephonic interview summary provided with 1/31/22 Non-final Office action).
In view of the new claims 124-129 and their scope, the examiner notes that Applicant’s 6/21/22 election of sodium as the ion and including a concentration range thereof, pertaining to claim 103, is moot based on cancellation of claim 103 and no identified plural ions in the single independent new claim 124, and its only dependent claim 128, that narrows to two ions, potassium and sodium, without concentration ranges.
Claim 126 was withdrawn as not being directed to the elected EMR species of surgical procedure.
Claim Status
Claims 72, 92-97, 99-102, 124 are pending.
Claims 1-71, 73-91, 98, 103-123 and 125-129 are cancelled.
Claims 72, 92-97, 99-102 are withdrawn as being directed to a non-elected invention(s).
Claim 124 is pending and under examination.
Claim 124 is rejected.
Priority
The instant application, filed 11/11/2019, having 1 RCE-type filing, is a division of 14773262, filed 09/04/2015, now abandoned and having 1 RCE-type filing therein
14773262 is a national stage entry of PCT/IB2014/059496, International Filing Date: 03/06/2014
PCT/IB2014/059496 Claims Priority from Provisional Application 61773359, filed 03/06/2013.
Information Disclosure Statement
The Examiner has considered the reference(s) provided in the 3/13/26 Information Disclosure Statement, and provides a signed and dated copy of such herewith.
Entry of Specification Amendment
For clarity of the record, the examiner has provided an “OK to Enter” with initials and date on the cover page for the 2/12/2020 amendment to the specification.
Claim Objections
Applicant’s arguments, see page 5, filed 3/13/26, and claim amendments, with respect to the objections to claim 124 have been fully considered and are persuasive. The objections to claim 124 have been withdrawn.
Claim Interpretation – Retained for the Record
The claim limitations are given their broadest reasonable interpretation (BRI) consistent with the specification, MPEP 2111, and under the BRI, words of the claim must be given their plain meaning, unless such meaning is inconsistent with the specification, MPEP 2111.01.
The single independent claim under current examination, claim 124, is directed to a method of preventing post-operative bleeding after a surgical procedure performed on a human patient dosed with an anticoagulant …, and the last line of claim 124 states “thereby preventing post-operative bleeding after the surgical procedure, wherein the surgical procedure is EMR or ESD” (emphases added).
The specification does not define “preventing”.
The Google-searched Oxford languages definition of prevent is “keep (something) from happening or arising,” copy previously provided.
In the context of what is claimed, a consideration of the knowledge in the art is relevant to setting forth an appropriate definition of “of preventing” in the context of what is being claimed.
The claim is directed to any surgical procedure on a human patient as long as that patient has been “dosed with an anticoagulant”, which has no timing as to the dosing, nor the purpose of the dosing, but is interpreted given the knowledge in the art as the dosing occurring prior to the surgery for the purposes of the surgical procedure. The methods’ preventing post-operative bleeding is not limited temporally nor to the surgical site.
Pavie, Ann Thorac Surg 1999;68:705–10, previously provided, teaches that most bleeding in cardiovascular surgery “is biological, not surgical, the result of disseminated intravascular coagulation in its latter phases,” Background. The title clearly indicates managing postoperative bleeding. Among major factors taught to affect bleeding during implantation type surgeries is anticoagulation therapy, page 705, so Pavie’s teaching includes claimed surgical procedures. There is no reasonable basis to consider that the claimed administration of a composition comprising RADA-16 at the site of a bleeding surgical site would prevent disseminated intravascular coagulation (DIC), this located away from such surgical site, that occurs after the surgical procedure, that is, that are postoperative.
Even assuming the prevention of post-operative bleeding is intended to apply only to the surgical site that is bleeding (during the surgical procedure), the claim scope even when limited to EMR and ESD surgeries encompasses surgeries where the surgeon does not perform well, see Hammond and Margolin, CLINICS IN COLON AND RECTAL SURGERY/VOLUME 19, NUMBER 4 2006, 188-194, previously provided, quotation on page 188 from William Stewart Halsted, and/or the condition of the patient including his/her underlying hemostatic condition and/or nature of injury and surgery, and/or post-operative events, such as physical injury post-surgery, present a great challenge to prevent post-operative bleeding.
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.
Response to Arguments
Applicant’s arguments, see pages 6 and 7, filed 3/13/26, with respect to the rejection(s) of claim(s) under 35 USC 112(b)/112/2nd para, and also under 35 USC 112(d)/112/4th para have been fully considered and are persuasive in substantial part. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of newly introduced language.
Claim 124 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 124 recites step b) as "removing any extra composition formed by mixing of the gelled composition and blood from the site by washing the treated surgical site with a saline wash”.
Given the teachings of the specification, which in para 133 recites, “For example, peptide compositions may be washed with saline, allowing for repeated use during surgery” (this perhaps suggesting multiple complete removal of the RADA-16 hydrogel followed by re-application(s) thereof), which in para 135 recites “In some embodiments, the present invention provides the recognition that upon stoppage of bleeding during a surgical procedure or once all or substantially all tasks associated with the a surgical procedure have been completed, excess peptide composition described herein can simply be removed by washing with water” (note that this recites water not saline wash or rinse), which in para 326 recites “After the removal of extra Composition 1 using a saline wash, prevention of bleeding can be confirmed easily” (this not stating whether such “extra Composition 1” is in liquid or gelled form, nor whether it is mixed with blood, and the paragraph beginning with reference to oozing bleeding only, “Application of Composition 1 in advance or instantly to an oozing bleeding site will attain arrest of bleeding and prevent further bleeding, all of which contributes to a clear view of the surgical field”, please note that this is the only use of “extra” found in the application with regard to the administered peptides), and where para 185 in its entirety states, “Composition 1 is a clear, colorless liquid and retains this transparent quality upon application to a surgical site upon which the peptide solution adopts a gelled state by the formation of a hydrogel and has the ability to stop bleeding during the performance of a surgical procedure. This transparent quality makes Composition 1 uniquely suited for use in surgical procedures over other materials in terms of its ease of use and ability to maintain a clear surgical field. Composition 1 can be provided in a pre-filled syringe and thus is unique compared to other materials, e.g., fibrin glue, which needs to be prepared and mixed from separate liquids. There is no such requirement with Composition 1 as it is made from peptides and can be completely broken down by washing. The inventors have realized a number of advantages in employing Composition 1 in surgical procedures: virtually unlimited frequency of application, faster and more efficient control and stoppage of bleeding, maintenance of clear surgical field and bleeding site due to transparent quality, easily removed by irrigation, shortens duration of bleeding control measures during surgery, overall shortening of time required to complete surgical procedure, and may improve the rate of patient recovery by contributing to overall decrease in blood loss during surgery” (bold emphases added), it is unclear what the “extra composition formed by mixing of the gelled composition and blood” refers to, whether this step is conducted to remove only some portion of the gelled composition, whether this includes removal of blood that has reacted with the peptide (versus blood covering or otherwise associated with the gelled peptide/composition that has not reacted with the peptide), or whether at some point in the surgical procedure the “excess” is substantially all of the gelled form of the peptide, removed toward the end of the surgical procedure to assess status of bleeding based on a degree of “plugging” that may be internal to the treated tissue. What is the ‘extra’ that is being removed is neither clear nor evident at least because of a lack of explanation of what ‘extra’ signifies – too much gel, too thick gel, an overapplication of liquid RADA-16 solution, or something else. The metes and bounds of what is claimed in this step are unclear, rendering the claim indefinite and rejected under this section.
Although the examiner recognizes that the previous rejection included “This part of the rejection can be overcome by removing “b)” and clearly making “removing” as a second active step of the claim,” what applicant has chosen for wording of step “b)” has introduced new confusion and lack of clarity (as well as a question of support, see rejection below).
Claim Rejections - 35 USC § 112 – Written Description
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.
Response to Arguments and Declaration/Affidavit
Applicant's arguments filed 3/13/26 have been fully considered but they are not persuasive.
The examiner also has considered the Declaration/Affidavit provided 3/13/26 and finds this not persuasive as explained herein.
As to applicant argument/response numbered 1, this is moot based on claim amendment.
As to applicant argument/response numbered 2, the issue of how claim 124’s step b), when combined with its step a), results in the “thereby” clause remains, in the examiner’s opinion, relevant to the claim, and does not appear to be moot simply based on removal of “anti-coagulation treatment” from the claim.
As to applicant argument/response numbered 3, flowing onto page 9, the examiner respectfully disagrees that the new claim language of step b) is “very clear”. See above rejection. There is no disclosure in the application as filed of “excess of blood would mix with solution, and may form a brownish gel of coagulated blood, which in turn may obstruct the camera view, but more importantly, site-of-surgery view.” Applicant’s underlined sentence in “a” on page 9 emphasizes a point of lack of clarity – is what is being claimed to be removed some type of “excess”, or the entire gelled composition mixed with blood, which has obstructed the field of view (so that there is repeated addition of peptide solution – “repeated use”), or something else?
Part b on page 9 needs no response by the examiner.
As to part c on page 9, the examiner does not dispute any Written Description requirement law or policy, however does dispute that there is support in the specification as filed, including when considering what the PHOSITA could “readily envisage” and what the prior art knowledge provides.
As to part d on page 10, somewhat related to part c on page 9, applicant appears to want to have it “both ways” – that the PHOSITA can “readily envisage” what is claimed, but that this “would not have come from the general knowledge in the art or experience with some other hemostats …”. The examiner does not find this line of reasoning persuasive given what he perceives upon review of the application as filed, including when considering what the PHOSITA can “readily envisage”, based on a lack of support for what is claimed after consideration of the application as filed, this further problematic when combined with lack of clarity, see above. The stated “use of washing multiple times” and various surgeries does not support that is instantly claimed.
With regard to Marc Dean’s declaration/affidavit and its statements regarding rejection under this section, the examiner only finds para 7 to be relevant, and this is based on Dr. Dean’s “personal knowledge and experience”, and that opinion is “that PHOSITA could readily envisage using a saline wash post-procedure, …”. The examiner does not find other statements in the declaration/affidavit relevant to the rejection under this section, and does not disagree with the quoted statement. Weighing other evidence, such as found in the application as filed, against attorney’s statement and Dr. Dean’s limited statements as to this rejection, and given the lack of clarity as to what is being removed in step b) and possession thereof, neither attorney’s statement nor Dr. Dean’s statements and explanations are persuasive.
Claim 124 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The following set forth the bases for lack of possession of what is claimed across the scope of what is claimed:
Re combination of claimed limitations: Claim 124 is directed to a claimed ‘thereby’ result of reducing all postoperative bleeding for EMR and ESD types of surgeries performed by all surgeons on a human patient, wherein the surgical site is bleeding, the method comprising a step of application of the composition of part a) of claim 124 to a surgical site, followed by step b) “removing any extra composition formed by mixing of the gelled composition and blood from the site by washing the treated surgical site with a saline wash.”
The specification separately teaches (all para numbers of corresponding PGPUB 20200164100) the following.
“Saline” or “saline solution” appears in paras 133 “For example, peptide compositions may be washed with saline, allowing for repeated use during surgery,” this comparing to existing materials such as fibrin glue, 273, referring to removing blood “…to ensure the surgical field can be viewed clearly in order to apply SURGICEL®”, 288 regarding injecting saline during EMR procedure, para 310 when contrasting with SURGICEL® when applied to the connecting tissue of renal artery, stating “Alternatively, Composition 1 can be removed by washing with saline,” and related to the same renal artery procedure in para 311, “Complete control and stoppage of bleeding can be confirmed by removing an excess amount of Composition 1 by washing with saline before closing the abdominal cavity” (please note that this refers to removing “an excess amount” whereas claim 124 claims “removing extra composition formed by mixing of the gelled composition and blood”), and paras 323, 324, and 326 used for arresting bleeding encountered during stripping in Example 13’s Laparoscopic Partial Nephrectomy, this including removal of “extra Composition 1 using a saline wash.”
Please note that para 316 states in part, “Composition 1 has the potential to operate as a prevention of post-surgical bleeding control without the need for washing after application,” yet what is claimed requires “removing any extra composition formed by mixing of the gelled composition and blood from the site by washing the treated surgical site with a saline wash.”
Para 326 states the following, “Application of Composition 1 in advance or instantly to an oozing bleeding site will attain arrest of bleeding and prevent further bleeding, all of which contributes to a clear view of the surgical field. Surgical procedure time is decreased by the substitution of Composition 1 for traditional, and often complicated, bleeding control measures such as SURGICEL® and fibrin glue. After the removal of extra Composition 1 using a saline wash, prevention of bleeding can be confirmed easily. Further, by applying Composition 1 to the circumference after the suture of the renal calyx, post-bleeding prevention is achieved.” This is the only location found by the examiner where there “removal of extra Composition 1 using a saline wash” is set forth, and here there is no reference to removing “any extra composition formed by mixing of the gelled composition and blood” as claimed. What is taught in para 326 is “removal of extra Composition 1 using a saline wash”, and what this means, whether Composition 1 in liquid or gelled form, is neither clear nor evident at least because of a lack of explanation of what ‘extra’ signifies – too much gel, too thick gel, an overapplication of liquid RADA-16 solution, or something else (see rejection above). This paragraph refers to oozing bleeding and is silent on reduction of post-operative bleeding. Considering what is set forth in the application as filed, while considering the knowledge in the art, there is a lack of possession of what is instantly claimed in step b) as a stand-alone limitation as well as when also considering the thereby clause.
Please note that when limitations are claimed in combination in a claim, cobbling together support from unrelated parts and paragraphs of the application, and/or from examples in the application is not sufficient to support possession of such combination.
Critically, in Example 3 that provided data regarding at least some results for non-existence of post-operative bleeding, which per above does not appear to be ESD nor EMR, and for which the parameters were not elucidated, there was no disclosure of the composition having been removed (either completely, including the gelled state, or only the excess material/ungelled composition, or some mixture with blood) by “washing the treated surgical site with a saline wash”. As such, there is no reasonable basis to conclude applicant had possession of the method claimed in claim 124 for the scope of what is claimed, and claim 124 is rejected at least on this basis under this section.
Further regarding breadth of post-operative bleeding in view of what is claimed: As clearly taught in Pavie, Ann Thorac Surg 1999;68:705–10, previously provided, most bleeding in cardiovascular surgery “is biological, not surgical, the result of disseminated intravascular coagulation in its latter phases,” Background. The title clearly indicates managing postoperative bleeding and disseminated intravascular coagulation (DIC) and consequent bleeding resulting after a surgical procedure, “the result of DIC in its later phases,” page 705 and elsewhere. Among major factors taught to affect bleeding during implantation type surgeries is anticoagulation therapy, page 705, so Pavie’s teaching includes certain surgical procedures. There is no reasonable basis to consider that the claimed administration of a composition comprising RADA-16 at the site of a bleeding surgical site would prevent disseminated intravascular coagulation (DIC), this located away from such surgical site, that occurs after the surgical procedure, that is, that are postoperative. Nor would step b) of claim 124 by any logical reasoning lead to a basis for preventing or reducing DIC so as to reduce post-operative bleeding. Accordingly, there is a lack of possession based on the lack of effect of administering the claimed composition to the bleeding surgical site, and the removing step b) with a saline wash, to post-operative bleeding that is remote from such site, including the lack of evidence in the application as filed that indicates the effect of administering the composition to the bleeding surgical site on post-operative DIC. As to the effect of the method of claim 124 on post-operative bleeding more directly associated with the surgical procedure itself, as set forth above regarding Example 3, for which the parameters were not elucidated, there was no disclosure of the composition having been removed (either completely, including the gelled state, or only the excess material/ungelled composition, or some mixture with blood) by “washing the treated surgical site with a saline wash”. Any effect on reducing post-operative bleeding does not appear related to the entirety of what is instantly claimed.
Based on the above, claim 124 is rejected at least on the bases under this section.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived 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 pre-AIA 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Response to Arguments and Declaration/Affidavit
Applicant’s arguments with respect to claim(s) 124 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Please also note that referring to Dr. Dean’s Declaration, page 12, specifically to the PURASTAT® IFU, neither applicant nor Dr. Dean indicates why the ‘before’ precaution (of a document having a date post-filing) would be expected to be a teaching against an ‘after’ rinsing once the gel has already formed. This appears not relevant when also considering the knowledge in the art regarding rinsing of other hemostats used during surgical procedures, and additionally when the amount of rinsing reasonably would affect how much of any hemostat, including a RADA type, is removed at any time during any surgical procedure. This applies to multiple statements on pages 12-14 of applicant’s 3/13/26 Remarks. Adding a small amount of unbuffered saline would not remove a substantial amount of already gelled peptide, the amount of rinsing reasonably is within the realm of KITA by surgeons in the relevant field, and applicant has not provided evidence to the contrary. Neither applicant nor Dr. Dean has indicated the pH of the gelled peptide after gelling from contact/exposure to blood, which is buffered, although para 10 of Dr. Dean’s declaration/affidavit appears to support that the gelled peptide (after contact with buffered blood) does not have a strongly acidic characteristic. (While clearly not dispositive, it seems to the examiner that if the pH of the gelled peptide were too low, it would be inflammatory and not conducive to healing. Further to this non-dispositive point, it appears to the examiner that once gelled, rinsing with unbuffered saline would not lower the pH substantially because the gelled peptide having been in contact with the buffered blood would not have enough acidic nature to lower the pH of the unbuffered saline wash.)
The examiner also has considered the Declaration/Affidavit provided 3/13/26 and finds this not persuasive as explained herein.
All statements and arguments by Dr. Dean against previously applied references are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record.
Regarding para 11, this pertains to mixing with RADA solution, which is not claimed and does not appear relevant to the issues at hand. In contrast to what Dr. Dean proposes as an hypothetical by asserting that unbuffered saline solution “will not maintain its pH when 1-5 mls of RADA-16 solution (pH=2.4) is added”, Gelain et al., Journal of Controlled Release 145 (2010) 231–239, teaches that its RADA 16-I pH was 7.4, versus a calculated 8.1, see Table 1, page 231 and associated text. Also see Ye et al., J. Pept. Sci. 2008; 14: 152–162, entire text and particularly Figure 2, page 155, and associated text. From these references a hydrogel formed from RADA-16 has a pH around neutral. No evidence has been provided, nor any reasonable argument or basis presented, that when adding saline rinse to an already gelled RADA peptide that the pH lowers to approximately pH 31. As such, what is stated in para 11 and the conclusion in para 12 do not appear relevant nor dispositive to what is instantly claimed in claim 124.
Regarding paras 13 and 14, as noted by applicant discovery of a mechanism is not dispositive to allowance of a claim. The conclusion sentence at the end of para 14 has been considered but the examiner does not find this persuasive given the knowledge in the art about gelation of the RADA peptide and the use of saline wash/rinses in the prior art.
Claim 124 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Ellis-Benkhe et al., Nanomedicine: Nanotechnology, Biology, and Medicine 2 (2006) 207– 215 (EBK, previously provided) in view of Lepilliez et al., Endoscopy 2008 40:806-810, supplied in 2/12/2020 IDS (Lepilliez), Zimmerman et al., Scan J Gastroenterol. 1994;29:795-798, Abstract only (Zimmerman), Robson and Steed, Current Problems in Surgery, vol. 38, No. 2, 2001, pp 73-140 (Robson), Song et al., Macromol. Biosci. 2010, 10, 33–39 (Song), and US 2009/0062233, Ji et al., published 3/5/2009 (Ji).
Claim 124 is directed to “A method of reducing post-operative bleeding after an endoscopic surgical procedure at the site of the procedure performed on a human patient, wherein the surgical site is bleeding, the aforesaid method comprising:
a) applying an ungelled peptide solution comprising about 1% to about 3% (w/v) of a peptide having an amino acid sequence of n-RARADARADARADARADA-c (SEQ ID NO:4); and wherein the solution is characterized by an ability to a gelled state adopted when the peptide solution comes in contact with the patient’s blood, and
b) removing any extra composition formed by mixing of the gelled composition and blood from the site by washing the treated surgical site with a saline wash;
thereby reducing post-operative bleeding following the surgical procedure, wherein the surgical procedure is endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD).”
EBK teaches and vividly demonstrates the highly effective hemostatic properties and capabilities when administering ungelled solutions of the same RADA-16 as claim 124’s SEQ ID NO:4, see Abstract, Figs. 1-3. In Figure 3 sagittal and transverse cuts to rat liver were made, resulting in reported profuse bleeding that nonetheless was stopped rapidly by administering 1%-4% solutions of NHS (which per page 210 is RADA-16). Per Fig. 3 legend, the bleeding of the sagittal cut completely stopped in 8.6 seconds, compared to 90 seconds for cauterization, and the bleeding of the transverse cut ceased within 10-11 seconds using any of the 2-4% solutions. See also Figure 4 which also dramatically demonstrates the effectiveness of the same solution as claimed, in the same concentration range, to stop bleeding. This overall demonstrates much superior results compared with the cauterization approach often used in surgeries. This also meets claim 124’s “wherein the solution is characterized by an ability to a gelled state adopted when the peptide solution comes in contact with the patient’s blood” at least based on the liver bleeding experiment, on EBK teaching that its method to stop bleeding based on self-assembly at the nanoscale “results in the formation of a nanofiber barrier that stops bleeding in any wet ionic environment in the body,” and also based on the fundamental issue that the identical chemical solutions have the same properties.
EBK does not explicitly teach its method to stop bleeding as claimed is for reducing post-operative bleeding for the elected EMR procedures.
The level of ordinary skill in the pertinent art is moderately high.
Lepilliez teaches that endoscopic mucosal resection (EMR) is used for endoscopic resection of sporadic duodenal adenoma (SDA), and concluded that this endoscopic resection “is an efficient and acceptably safe technique for treating SDA”, page 806. Lepilliez teaches that during its EMR procedures by experienced surgeons hemostasis was performed for “intraprocedural” bleeding either using an epinephrine injection, clipping with hemoclips, or monopolar electrocoagulation, page 807. The clear implication of “intraprocedural” is that some surgical procedure was performed after addressing bleeding. When bleeding occurred after the EMR “it was defined as “delayed” bleeding and a second-look endoscopy was then performed for hemostasis. Id. Prophylaxis for such bleeding was done using either argon plasma coagulation (APC) or by primary closure of the resection site using hemoclips. Id.
On page 810 Lepilliez concludes, “Evolving devices and techniques that will permit not only resection but also hemostasis and closure of the resection site will certainly lead to important improvements in this technique in the future, and duodenal EMR, like other complex endoscopic therapies, will be increasingly considered to be an endoluminal surgical procedure.”
The delayed bleeding reported in Lepilliez occurred following five EMR procedures, representing 11.6% of the procedures, and occurred within 10 hours, page 808. It appears that claim 124’s ‘thereby …’ closing clause addresses a small percentage of surgical procedures.
And Zimmerman concludes that for patients who underwent endoscopy due to acute upper GI hemorrhage, secondary hemorrhage was associated with increased mortality which “is related to the underlying diseases and not to a difference in the causes of bleeding.”
Robson, page 105, teaches that “for normal wound healing to occur, there must be an adequate blood supply. Local wound perfusion can be enhanced by the surgeon. Ischemia is known to inhibit wound healing.” (As to be discussed later, this leads to the logic of selection from among the methods employed to stop bleeding during a surgical procedure a method that allows for adequate blood supply would be favored over one that destroys blood vasculature.)
Taken together, the teachings of Zimmerman and Robson, with Lepilliez, suggest that if a surgical patient/subject were to have delayed post-operative hemorrhage/secondary bleeding, such person very likely would be someone having underlying diseases that limit blood flow and/or normal would healing factors present in sufficient amount for wound healing, see Robson Table 1, page 80, and associated text, and/or received a particular procedure during the surgical procedure that limited blood flow.
On page 810 Lepilliez concludes, “Evolving devices and techniques that will permit not only resection but also hemostasis and closure of the resection site will certainly lead to important improvements in this technique in the future, and duodenal EMR, like other complex endoscopic therapies, will be increasingly considered to be an endoluminal surgical procedure.”
Song further supports hemostatic use of RADA-16 set forth in EBK, albeit in a rodent model of kidney surgery. Song reports that whereas a competing hemostatic product, a gelatin sponge, “was cumbersome to use and crumpled easily,” and the 2% RADA-16 treatment “produced good hemostatic efficacy”, concluding that RADA-16 “may become a valuable tool for surgeons and emergency medical personnel as a hemostatic agent for minor bleeding or oozing wounds.”
Lepilliez suggests improvements to its hemostatic methods and reports about delayed bleeding as it occurred in its procedures. Based on the teachings of EBK and also Song, in view of the overall rapid effectiveness of RADA-16 and its ability to cover a wound or surgical site, one of ordinary skill in the art would have selected RADA-16 as a hemostatic agent for evaluation in a range of surgeries, including EMR. The concluding statement in Song provides a motivation to use this when dealing with oozing wounds, and is supported by Robson given that teachings need for blood flow to be retained (at least to some degree) for healing (versus more tissue-destructive hemostatic methods).
The prior art contained Lepilliez’s “base” method, upon which what is claimed (as reasonably understood) can be seen as an “improvement,” the prior art references EBK and Song contained a known technique that is applicable to Lepilliez’s EMR method, and one of ordinary skill in the art would have recognized that applying the known technique would have yielded predictable results and resulted in an improved system.
Given EBK’s strikingly effective result on both gushing and exudative/oozing bleeding, and Lepilliez’ s understanding and expectation that new hemostasis techniques would lead to improvements, and also its teaching of dealing with bleeding intraprocedurally, and Song’s further statement regarding use of RADA-16 for oozing bleeding, it would have been obvious to one of ordinary skill in the art to select RADA-16 solutions in the same concentration as used by EBK for controlling exudative bleeding during a laparoscopic or endoscopic EMR procedure and also performing at least part of the surgical procedure while the composition is in the gelled state in the surgical site. A further rationale is improving a known procedure by selecting a known hemostatic agent shown to be highly effective for a surgical procedure known to need to address intraoperative bleeding, this bleeding including exudative bleeding (supported by Lepilliez’ s use of electrocauterization in view of Romano’s teachings of such use for exudative/oozing bleeding).
Please also note that administering the same peptide solution necessarily would have the same effects, including regarding claim 124’s language “wherein the solution is characterized by an ability to a gelled state adopted when the peptide solution comes in contact with the patient’s blood.”
As to claim 124’s step b, Ji teaches it was routine to remove an extra hemostatic composition, for Ji this being a starch hemostatic material, from a surgical site by using a saline rinse, that is, where a modified starch possesses a hemostatic effect, used in “absorbable surgical wound sealing”, Ji teaches that, “Any excess modified starch not involved in hemostatic activity is readily dissolved and rinsed away through saline irrigation during operation,” Abstract, surgical procedures including when “delivered under laryngoscope, endoscope, and laparoscope,” para 28. A person of ordinary skill in the art, such as a surgeon performing an endoscopic procedure, would have considered such approach to using a saline rinse to remove extra, or excess, hemostatic material as a routine practice based on Ji’s teachings, and to incorporate it when needed in a particular procedure, whether to obtain a better field of view or for another reason, such as to remove that material not needed for hemostasis that already is under control.
Given the highly effective hemostasis using RADA-16 demonstrated by EBK, there would have been a reasonable expectation of success for stopping exudative or other types of bleeding during the surgery. Further, given that following another experiment in EBK, applying 3% RADA-16 to adult rat left lateral liver lobes after a 4 mm hole punch puncture, this achieving hemostasis within 10 seconds, Figure 4, B, versus more than 60 seconds for heat cautery, the RADA-16 treated animals were allowed to survive for as long as 6 months, and there was no detrimental effect on tissues, page 213 left column.
Given its much greater effectiveness for a variety of wound types evaluated in EBK, including in comparison to cauterization, there would have been a reasonable expectation of success to achieve what is claimed in claim 124.
Further as to yielding predictable results and resulting in an improved system/method, this is based on the exceptionally good performance of RADA-16 as a hemostatic agent in EBK, coupled with Song’s conclusion regarding oozing bleeding, combined with the already low incidence of delayed post-operative hemorrhage/secondary bleeding reported by Lepilliez, and the likelihood per Zimmerman and Robson that for such bleeding to occur “at least three days after the EMR surgical procedure,” such person very likely would be someone having underlying diseases that limit blood flow and/or normal would healing factors present in sufficient amount for wound healing, and for such person the selection of a non-tissue-destructive hemostatic approach, such as with RADA-16, would reasonably increase the likelihood of reduction of such bleeding. There would have been a reasonable expectation of success given the demonstrated effectiveness of RADA-16 both for gushing and oozing type bleeding.
Based on the above references and the rationales taken separately or collectively, claim 124 would have been obvious.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/JOSEPH FISCHER/Primary Examiner, Art Unit 1658
1 It is the examiner’s understanding that RADA-16 is provided in a strongly acidic solution to maintain fluidity and avoid forming a hydrogel before application. Once formed as a hydrogel when mixed with blood, or in the presence of particular ions, or at a surgical site where fluids are buffered and close to neutral pH, it seems to the examiner that the acidic medium of the RADA-16 solution would mix with bodily fluids, which are buffered, and at some time point thereafter the addition of unbuffered saline would not substantially alter the pH at and around the gelled RADA-16. It appears that Dr. Dean may have conflated the acidity of the solution with that of the formed hydrogel, or otherwise conceived of a situation that from the examiner’s perspective is not within the realm of what is being claimed given that the claim in step a) regards administering in a place and manner where the hydrogel would form (in contact with the patient’s blood), and only thereafter in step b) is there a removing step.
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